PHYSIOLOGICAL REVIEWS
Vol. 81, No. 3, July 2001
Printed in U.S.A.
Cerebellar Long-Term Depression: Characterization,
Signal Transduction, and Functional Roles
MASAO ITO
Brain Science Institute, RIKEN, Wako, Saitama, Japan
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I. Introduction (Historical Background)
A. Dissection of neuronal network in 1960s
B. Exploration of synaptic plasticity in 1970s to 1980s
C. System approach in 1970s to 1980s
D. Discovery of signal transduction and cognitive function in 1990s
II. Characterization of Cerebellar Long-Term Depression
A. Induction of LTD
B. Features as synaptic plasticity
III. Signal Transduction: Initial Processes
A. First messengers
B. Receptors
C. Ion channels
D. G proteins
E. Phospholipases
IV. Signal Transduction: Further Processes
A. Ion concentrations
B. Second messengers
C. Protein kinases and protein phosphatases
D. Other factors
E. Inactivation of AMPA receptor
F. Chemical network for LTD
V. Models for Functional Roles of Long-Term Depression
A. Corticonuclear microcomplex
B. Roles of GAs
C. Other types of synaptic plasticity
D. Accessory circuits
E. As an internal model
VI. Experimental Evidence for Functional Roles of Long-Term Depression
A. Error representation by CFs
B. Involvement of LTD in motor learning
C. Functional representation of PC activities
D. Consistency of LTD with learning
VII. Conclusion
Ito, Masao. Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles.
Physiol Rev 81: 1143–1195, 2001.—Cerebellar Purkinje cells exhibit a unique type of synaptic plasticity, namely,
long-term depression (LTD). When two inputs to a Purkinje cell, one from a climbing fiber and the other from a set
of granule cell axons, are repeatedly associated, the input efficacy of the granule cell axons in exciting the Purkinje
cell is persistently depressed. Section I of this review briefly describes the history of research around LTD, and
section II specifies physiological characteristics of LTD. Sections III and IV then review the massive data accumulated
during the past two decades, which have revealed complex networks of signal transduction underlying LTD. Section
III deals with a variety of first messengers, receptors, ion channels, transporters, G proteins, and phospholipases.
Section IV covers second messengers, protein kinases, phosphatases and other elements, eventually leading to
inactivation of DL-␣-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate-selective glutamate receptors that mediate
granule cell-to-Purkinje cell transmission. Section V defines roles of LTD in the light of the microcomplex concept
of the cerebellum as functionally eliminating those synaptic connections associated with errors during repeated
http://physrev.physiology.org
0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
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exercises, while preserving other connections leading to the successful execution of movements. Section VI
examines the validity of this microcomplex concept based on the data collected from recent numerous studies of
various forms of motor learning in ocular reflexes, eye-blink conditioning, posture, locomotion, and hand/arm
movements. Section VII emphasizes the importance of integrating studies on LTD and learning and raises future
possibilities of extending cerebellar research to reveal memory mechanisms of implicit learning in general.
I. INTRODUCTION
(HISTORICAL BACKGROUND)
A. Dissection of Neuronal Network in 1960s
Until around 1960, synaptic plasticity was a concept
of only theoretical importance, since there was no experimental evidence for it. Hebb (195) postulated that, in an
assembly of mutually interconnected neurons, synapses
activated synchronously, both presynaptically and
postsynaptically, are strengthened in their transmission
efficacy. Eccles (133), investigating posttetanic potentiation in the spinal cord, assumed that presynaptic activation alone is sufficient to potentiate synaptic transmission. Based on a set theory that includes possible
combinations of presynaptic and postsynaptic events,
Brindley (70) proposed the presence of 10 different types
of synaptic plasticity in the central nervous system, including the Hebb and Eccles types. It is noteworthy that
Brindley included long-term depression (LTD) under the
designation “habituation,” giving equal weight to potentiation and habituation. He also predicted synaptic plasticity in inhibitory synapses, which was not known to exist
until very recently (see sects. VC5 and VC8). To demonstrate the computational capability of a neuronal assembly, Rosenblatt (454) constructed a three-layered artificial
neuronal network capable of learning, called the “Simple
Perceptron,” which incorporated synaptic plasticity in
one layer.
B. Exploration of Synaptic Plasticity
in 1970s to 1980s
In the 1970s, two lines of evidence suggested the
presence of a synaptic plasticity in the cerebellum. We
observed that in the flocculus, an evolutionarily old part
of the cerebellum, MF pathways arising from the vestibular organs and CF pathways arising from the retinas
converge onto PCs (157, 224, 351). This unique pattern of
convergence suggests that a synaptic plasticity occurs in
the flocculus as causal to the remarkable adaptability of
the vestibuloocular reflex (VOR), and the observation
made in PCs of rabbits flocculus favored Albus’ hypothesis (128, 166, 167, 230). Gilbert and Thach (170) found
that, in a monkey adapting to compensate for a sudden
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Studies of the cerebellum have a long history well
documented in the monographs of Jansen and Brodal
(247) and Moruzzi and Dow (127). The elaborate structural organization of the cerebellum analyzed by Jansen
and Brodal (247) encouraged researchers toward exploration of its functional meanings. The enormous data of
classic lesion experiments compiled by Dow and Moruzzi
(127) suggested characteristic functional features of the
cerebellum as enabling us to learn to move smoothly and
accurately even at high speeds and without visual feedback. These earlier studies paved the way for the modern
cerebellar research to proceed in the directions to uncover the elaborate neuronal mechanism of the cerebellum and to define its roles in the entire nervous system
function. Brief history presented here overviews the
progress of cerebellar research made during the past four
decades toward these directions.
In the 1960s, the neuronal circuit of the cerebellum,
involving five types of neurons [Purkinje cells (PCs), basket, stellate, Golgi and granule cells], was dissected in
detail by morphological and microelectrode techniques,
as summarized by Eccles et al. (134). PCs were revealed
to receive two distinct excitatory inputs: climbing fibers
(CFs) and axons of granule cells (GAs) (135–137) (Fig. 1).
CFs originate from the inferior olive, while GAs relay
mossy fibers (MFs) originating from the brain stem and
spinal cord. Basket, stellate, and Golgi cells were identified as inhibitory neurons. The PCs providing the sole
output pathway of the cerebellar cortex were defined as
exclusively inhibitory upon their target neurons in the
vestibular and cerebellar nuclei (244 –246).
Convergence of numerous GAs and a single CF to
each PC is a characteristic unique feature of neuronal
circuitry in the cerebellum (Fig. 1) well known since Cajal
(74). Brindley (69) was the first who viewed this structure
as representing the Hebbian type of synaptic plasticity.
Because CF signals via the numerous junctions between a
CF and a PC (see sect. IIA1) could regularly excite PCs,
synchronous activation of the CF and GAs results in a
conjunction of presynaptic and postsynaptic excitation,
which might in turn lead to long-term potentiation (LTP)
of the GA-PC synapses. Marr (359) adopted this view in
developing his epochal network theory of the cerebellar
cortex. In view of the stable operation of the system,
however, Albus (15) suggested that the conjunction results in a depression instead of potentiation and conceived the neuronal circuit in the cerebellar cortex as a
pattern separator like the Simple Perceptron.
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FIG. 1. Connections in the cerebellar cortex drawn by
Ramon y Cajal. A part of Figure 104 of Cajal (74) is shown
with the right, left axis reversed to match Fig. 6. A, mossy
fiber; B, Purkinje cell axon; a, granule cell; b, parallel fiber;
c, Purkinje cell; d, climbing fiber. Arrows indicate the
supposed directions of signal flow. [Modified from Cajal
(74).]
C. System Approach in 1970s to 1980s
Although neuronal network theories developed by
Marr (359), Albus (15), and others help us to understand
computational mechanisms of elaborate neuronal networks in the cerebellum, control system theories help to
understand how the elaborate networks of the cerebellum
are utilized for controlling movements. Considering the
unique way of involvement of the cerebellum in control of
VOR, the author suggested that the cerebellum makes
feed-forward control possible by replacing the feedback
loop and that this replacement is effected due to a learning mechanism referring to “control error” signals conveyed by CFs (223, 225). That CF signals represent errors
was also suggested from two other viewpoints. Miler and
Oscarsson (375) proposed that the inferior olive acts as a
comparator for command signals from higher centers and
the activity these signals evoke at lower levels. Albus (15)
postulated that CFs convey teacher’s signal informing
PCs about their misperformance in conducting pattern
recognition like the Simple Perceptron. Current evidence
for the error representation by CFs is reviewed in section VIA.
Through the 1970s and 1980s, various simple forms of
motor learning involving the cerebellum such as adaptation in ocular movements, eye-blink conditioning, locomotion, and hand/arm movements were established as
model systems for studying mechanisms of motor learning. Thach (515) applied microelectrode techniques to the
cerebellum of awake animals and collected signals of
individual PCs correlated to these motor tasks that
the animals performs. A morphological study of the cerebellum by Voogd and colleagues (178, 179) led to a
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change in arm load, PCs changed their discharge patterns
in the manner predicted from Albus’ synaptic plasticity
assumption (sect. VIA5).
Nevertheless, earlier efforts devoted to demonstrating the occurrence of synaptic plasticity by conjunctively
stimulating GAs and CFs failed to reveal a significant
change in GA-PC transmission, which may be attributed
to the following two major reasons. The first reason appears to be the small extracellular field potentials representing GA-PC transmission. LTP had successfully been
detected in the hippocampus by recording synaptic
events extracellularly (57); however, because the field
potentials in the cerebellar cortex are ⬃10 times smaller
than those in the hippocampus, minor changes could have
been undetected. A later study using an averaging technique revealed a depression (by ⬃25%) in the field potentials of the in vivo cerebellum (234) and cerebellar slices
(88). The second reason could be the vulnerability of
LTD to various factors that might block its induction
(see sects. III and IV).
In the early 1980s, an analysis of the firing index of
PCs in in vivo cerebella of rabbits revealed the presence
of LTD (138, 241). When the stimulus for MFs or GAs was
critically set at a threshold for exciting a PC, LTD was
sensitively reflected in the lowering of the probability of
firing in the PC. Later, LTD was also detected by recording
GA-induced events in PCs either extracellularly (234) or
intracellularly (459) and was eventually established as a
distinct type of synaptic plasticity near the end of the
1980s (228). Different types of LTD were also reported to
occur in the hippocampus and cerebral neocortex (65; see
also Ref. 26).
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D. Discovery of Signal Transduction and Cognitive
Function in 1990s
In the 1990s, owing to marked advancements in cellular physiology, biochemistry, and molecular biology, the
complex signal transduction mechanisms of LTD have
become a major research theme in neuroscience, as reviewed in sections III and IV. The advancement in knowledge of LTD signal transduction mechanisms provides
new tools for investigating functional roles of LTD in
various forms of cerebellar learning, as reviewed in section VI. In the 1990s, a new development in cerebellar
studies was the expansion of cerebellar roles to cognitive
functions. Such roles were proposed based on anatomical
connections of the cerebellum with the cerebral association cortex (309, 310), and the author supported this view
by analogies in movement and thought from a control
system viewpoint (229). Experimental evidence for the
involvement of the cerebellum in certain mental functions
now accumulates in studies applying noninvasive measurements and advanced clinical examinations to a variety of human mental activities including language (146),
attention (16), cognitive affective syndromes (466), fear
and anxiety caused by threats of pain (436), thirst sensation and fear for air hunger (426), and motor relearning
(221).
This review focuses on the major results of investigations conducted during the past two decades on the
characterization of cerebellar LTD, its signal transduction
mechanisms, and roles in cerebellar functions. Based on
analyses of the available data, the review aims to clarify
the targets of LTD studies in the forthcoming decades, in
particular, the relationship of LTD with permanent memory and roles of LTD in not only physical but also mental
activities.
II. CHARACTERIZATION OF CEREBELLAR
LONG-TERM DEPRESSION
A. Induction of LTD
1. GA and CF synapses on PCs
GAs consist of segments ascending from the granular
layer to the molecular layer and the bifurcating parallel
fiber (PF) branches that run along the molecular layer
(Fig. 1). A recent study revealed that PFs extend for 2–3
mm to each side of the bifurcation point, much longer
than previously thought. Functional implication of this
long PF projection is discussed in section VB2. Previously,
PFs were assumed to provide the sole GA inputs to PCs,
but Llinás (334) proposed a substantial contribution of the
ascending axons to GA-PC transmission. Functional implication of the asending segments of GAs is discussed in
section VB1.
While each PC was reported to receive 60,000 – 80,000
synapses on their dendritic spines, generally, one synapse
from one PF (424), more recent data in rats indicate that
each PC receives as many as 175,000 PF synapses (405,
406). In contrast, each PC comes into contact with only
one CF via numerous discrete synaptic junctions formed
on stubby dendritic spines (424). Multiple innervation of a
PC by CFs occurs during early development or in abnormal conditions such as genetic deficiency (see sect. VIB4).
The number of junctions formed between a CF and a PC
has been calculated as ⬃300 in the frog cerebellum (335).
In the rat cerebellum, the number of synaptic junctions
formed per 100-␮m length of PC dendrites is 11.45 for GAs
and 1.7 for CFs (412). This may suggest that as many as
26,000 synaptic junctions are formed between a CF and a
PC in rat. Since, however, CFs do not reach peripheral
portions of PC dendrites (424), this would give an overestimate.
2. Electrical signals that induce LTD
When recorded extracellularly in vivo, PCs generate
two different types of spikes. Simple spikes discharge at a
rate of 50 –100 Hz, and complex spikes, in a form of short
burst of spikes, occur at irregular, low rates around 1 Hz
(515). Stimulation of GAs elicits simple spikes (Fig. 2A),
whereas stimulation of CFs evokes complex spikes (Fig.
2B). When recorded intracellularly, PCs produce Na⫹
spikes and Ca2⫹ spikes (337, 338). The extracellularly
recorded simple spikes are Na⫹ spikes generated in the
somatic region and passively spread into the dendrites
(Fig. 2C). This earlier notion has been supported by dual
patch recording from somata and dendrites (500), and
also using sodium-binding benzofuran isophthalate
(SBFI) as a specific indicator for Na⫹ (77); the changes in
intracellular sodium concentration ([Na⫹]i) associated
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remarkable finding that, in addition to the classic lobular
structure, the cerebellum consists of a longitudinal compartmental structure including seven major zones (A, B,
C1, C2, C3, D1, and D2). Oscarsson (422) electrophysiologically defined a small, functionally uniform longitudinal area, called microzone, as a module of the cerebellar
cortex.
Efforts were devoted earlier to understand global
functional meanings of the unique anatomical architecture of the cerebellum such as the interconnection between the cerebellum and the cerebral cortex via thalamus, red nucleus, and pontine nucleus (17, 145, 223, 496).
The unique cerebrocerebellar communication loop was
interpreted as representing an internal model simulating
the limb and its spinal motor centers (223, 227) (see sect.
VE). These initial efforts are rewarded by the remarkable
development of computational approach to the cerebellum in the 1990s (275, 276, 372, 558).
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with antidromically or intrasomatically evoked Na⫹
spikes were confined to the cell somata. CF responses are
large excitatory postsynaptic potentials (EPSPs) due to
the numerous synapses made by a single CF on the PC
dendrites, superposed with somatic Na⫹ spikes followed
by smaller Ca2⫹ spikes (337, 338) (Fig. 2D).
GA impulses evoke two pharmacologically distinct
types of synaptic potentials in PCs. One is mediated by
DL-␣-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate
(AMPA)-selective glutamate receptors (see sect. IIIB1)
(Fig. 2E) and the other by metabotropic glutamate receptors (mGluRs) (sect. IIIB3) (Fig. 2F). AMPA-EPSPs are fast
and distinctly evoked by individual GA impulses, whereas
mGluR-EPSPs are slow and observable after a brief tetanus of GAs (8 pulses at 50 Hz) in the presence of an AMPA
receptor antagonist (39, 40). The size of the AMPA-mediated excitatory postsynaptic currents (AMPA-EPSC) generated by a single GA-PC synapse was estimated in cerebellar slices to be 2– 60 pA (34).
LTD in GA-PC transmission is indicated by persistent
reduction of the firing index of a PC in response to GA
stimulation in extracellular recording, the initial rising
slopes of GA-evoked AMPA-EPSPs in intracellular record-
ing (Fig. 3), or the size of GA-evoked AMPA-EPSCs (Fig.
4A) or spontaneously arising miniature EPSCs (mEPSCs)
(Fig. 4C), in whole cell clamping.
3. Conjunctive, homosynaptic, and
heterosynaptic LTD
The major subject of this article is the special type of
LTD induced at GA-PC synapses when GAs are repeatedly
activated in conjunction with the CF converging onto the
same PC. In view that the LTD is induced in those GA-PC
synapses involved in conjuntive stimulation, it is homosynaptic, but in the sense that the LTD requires activation
of CFs, it is heterosynaptic. It may be called conjunctive
LTD, as needed.
GA-PC synapses also exhibit homosynaptic LTD
when a relatively large set of GAs is repetitively stimulated without involving CFs (188). However, as long as
GAs are moderately stimulated, LTD occurs only after
GA-CF conjunctive stimulation (265, 381). Homosynaptic
LTD also occurs in CF-PC transmission during stimulation of CFs at 5 Hz for 30 s (184), but not during 1-Hz
CF/GA stimulation used for inducing conjunctive LTD
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FIG. 2. Electrical signals of Purkinje cells. Extracellular (A and B) and intracellular (C–F) recording from Purkinje
cells (PCs) are shown. A: simple spikes induced by stimulation of parallel fibers (PFs) on the pial surface of a cerebellar
folium. Two sweeps are superimposed. [From Eccles et al. (135). Copyright 1996 Springer-Verlag.] B: complex spike
evoked by stimulation at the inferior olive. [From Eccles et al. (137).] C: Na⫹ spike evoked by stimulation of granule cells
(GAs). [From Eccles et al. (136). Copyright 1996 Springer-Verlag.] D: climbing fiber responses composed of an excitatory
postsynaptic potential (EPSP) and Na⫹ and Ca2⫹ spikes. [From Eccles et al. (137).] E: AMPA-EPSPs evoked by
stimulation of GAs. [From Karachot et al. (265). Copyright 1994 Elsevier Science.] F: mGluR-EPSPs evoked by repetitive
stimulation of GAs in the presence of an AMPA antagonist. [From Miyata et al. (381). Copyright 1999 Cell Press.]
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FIG. 3. Long-term depression (LTD) observed in
PCs in cerebellar slices. Inset: EPSPs induced by stimulation of GAs. Six traces of EPSPs recorded before
(control) and 10 –50 min after conjunctive CF/GA stimulation are superimposed. Each trace indicates EPSPs
averaged for 5 sweeps repeated every 5 s. The graph
plots the rising slopes of the EPSPs against time.
Shaded column indicates conjunctive climbing fiber/GA stimulation. [Modified from Karachot et al.
(267).]
4. Stimulus parameters
The optimal condition for inducing conjunctive LTD
in the cerebellum in vivo is a 100-pulse stimulation of CFs
and GAs at 4 Hz with a CF-to-GA stimulus interval of
125–250 ms (139, 265). In cerebellar slices, simultaneous
GA/CF stimulation at 1 Hz for 5 min (300 pulses) was
optimal in the presence of a GABAA antagonist (picrotoxin) (265). In the absence of a GABAA antagonist, 600
pairings at 1 Hz of GA and CF stimuli within ⫾250-ms
intervals were required for effectively inducing LTD,
while 100 pairings were sufficient in the presence of the
GABAA antagonist (bicuculline) (88).
Although stimulation of GAs simultaneous with or
after CF stimulation LTD is usually used for inducing
LTD, whether a GA stimulus preceding a CF stimulus is
effective in inducing LTD or not is often questioned. This
question has been addressed in studies in which the
GA/CF stimulation intervals were systematically changed
(88, 139, 265). However, the results of such studies are
inconclusive, because GA/CF stimulation intervals cannot
be determined uniquely during repetitive GA/CF stimulation; for example, at 1-Hz stimulation, a GA stimulus
preceding a CF stimulus by 100 ms follows the preceding
CF stimulus with a 900-ms delay. Such a second-order
effect may be reduced if the stimulus frequency is lowered. However, this strategy is not realistic because at a
frequency lower than 1 Hz, conjunctive stimulation be-
comes less effective in inducing LTD (265). Unless an
appreciable LTD can be induced by the conjunction of
one GA stimulus and one CF stimulus, it is difficult to
define a GA/CF time relationship.
To natural stimuli, GAs respond repetitively, and CFs
often respond in the same way. Hence, there could be
probabilities of overlap between a series of GA and CF
impulses even when the MF- and CF-activating natural
stimuli are not critically timed. It should also be kept in
mind that GA and CF impulses produce complex signal
transduction processes in PCs, as reviewed in sections III
and IV, some of which could be sufficiently long lasting to
provide a conjuction between GA-induced and CF-induced signal transduction. Schreurs et al. (468) successfully induced LTD in rabbit cerebellar slices by applying a
series of 8 pulses (79 s, 100 Hz) to GAs and immediately
thereafter 3 pulses (20 Hz) to CFs, 20 times at 30- to 40-s
intervals. Wang et al. (539) also induced LTD in rat cerebellar slices by applying three to eight pulse stimuli to
GAs followed by a single pulse stimulus to CFs within
50 –200 ms. These GA-CF timing relationships are consistent with behavioral timing in motor learning (sect. VI, A2,
B2, and C1). Although the reason why our previous study
on rat cerebellar slices applying 15 pulses at 50 Hz to GAs
and immediately thereafter 3 pulses at 50 Hz to CFs,
repeated every 20 s for 10 min, failed to induce LTD (265)
is unclear, the stimulus conditions for LTD induction need
to be further explored in connnection with stimulus parameters and pharmacological environments, in which
cerebellar tissues are placed.
5. Interaction with postsynaptic inhibition
Induction of GA/CF-induced LTD in the cerebellum
in vivo was effectively blocked when the inhibitory
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(265). Functional meanings of these types of homosynaptic LTD is discussed in section v, C1 and C4. When
conjunctive or homosynaptic LTD occurs in a set of GAPC synapses, LTD is also induced in the neighboring
GA-PC synapses (445, 539). Functional meanings of this
heterosynaptic type of LTD are discussed in section VC2.
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postsynaptic potentials (IPSPs) were concomitantly induced in PCs by stimulation of off-beam PFs (138). This
effect is apparently related to the shortening or abolition
of long-lasting plateau potentials, which represent Ca2⫹
currents evoked by CF impulses. Imaging of intracellular
Ca2⫹ concentration ([Ca2⫹]i) with fura 2 demonstrated
that IPSPs strongly reduced the CF-associated increase of
[Ca2⫹]i in PC dendrites (76). In cerebellar slices, this
complication is usually avoided by blocking IPSPs with a
GABAA antagonist (picrotoxin or bicuculline). However,
even in the absence of a GABAA antagonist, GA stimulation with intermittent tetanic high-frequency effectively
induced LTD (265, 484). In the cerebellum in vivo, LTD
induction was not disturbed unless relatively large IPSPs
were evoked by electrical stimulation (138). These observations refute the suggestion that the LTD induced in
cerebellar slices treated with a GABAA antagonist is not a
physiological phenomenon.
B. Features as Synaptic Plasticity
1. Postsynaptic origin
Because the glutamate sensitivity of PCs undergoing
LTD was persistently depressed after the conjunction of
CF stimulation and ionotophoretic application of glutamate, GA/CF-induced LTD has been ascribed to a reduction in the efficacy of postsynaptic glutamate receptors
mediating GA-PC transmission (241). That a reduced form
of LTD (sect. IIB3) can be induced in cultured PCs in the
absence of presynaptic elements confirms that LTD occurs entirely postsynaptically. Metabotropic glutamate receptors subtype 4 (mGluR4) are distributed in the molecular layer along the presynaptic membrane of GAs (284,
363). Mice deficient in mGluR4 exhibited impairment of
the GA-induced paired-pulse facilitation and posttetanic
potentiation in PCs, whereas LTD was not impaired (428).
This indicates that LTD induction does not involve the
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FIG. 4. Reduced form of LTD in cultured PCs. Inset: diagram shows arrangement of two pipettes, one for recording
(M) and the other for iontophoresis of glutamate (I) on a PC. A and B: glutamate-induced potentials in cultured PCs. A:
3 cases of glutamate-induced currents recorded before (1), 10 min after (2), and 40 min after (3) glutamate/depolarization conjunction, showing no depression (a), short-term depression (STD) (b), or LTD (c). B: plotting the amplitudes of
glutamate-induced potentials against time before and after glutamate/depolarization conjunction. Perfusion with phospholipase (PL) A2 inhibitors changed LTD to STD. U73122, inhibitor of PLC. [A and B from Linden (322). Copyright 1995
Cell Press.] C and D: miniature excitatory postsynaptic currents (mEPSCs) recorded from cultured PCs. C: specimen
records of mEPSCs before (a), 2 h after (b), and 168 h after (c) 5-min conditioning treatment with 50 mM K⫹ and 100
␮M glutamate. D: changes of mEPSC amplitudes induced by 5-min treatments twice with a 30-min interfval. Each point
represents data from 9 –35 cells. [C and D from Murashima and Hirano (395). Copyright 1999 Society for Neuroscience.]
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mGluR4-regulated presynaptic mechanism for maintaining synaptic efficacy during repetitive activation. GAs express cannabinoid type 1 receptors (CBR1s) and their
mRNAs, and selective CBR1 agonists markedly depress
GA-PC transmission (313). CBR activation reduced transmitter release at GA-PC and CF-PC excitatory syanpses by
modulation of presynaptic voltage-gated channels, and
also at inhibitory synapses in PCs by not only presynaptic
voltage-gated channel modulation but also suppression of
the vesicle release mechanisms (505). CBR agonists also
partially inhibited GA/Ca2⫹ spike-induced LTD (313), but
how the presynaptic CBR1s are linked with LTD induction is unclear at present.
When the vestibular nerve on one side was stimulated in conjunction with stimulations of CFs at the inferior olive, LTD was observed in the flocculus PCs only in
their responses to stimulation of that nerve, but not of the
other vestibular nerve (241). When two PF beams were
differentially stimulated at a distance of 100 –200 ␮m in in
vivo cerebellum (138, 256) or 300 ␮m in cerebellar slices
(88) in the direction perpendicular to the PF beams, LTD
was induced only in the PF beam involved in conjunctive
stimulation with CFs. In cultured PCs, a reduced form of
LTD (see below) occurred only on the part of the dendrite
exposed to stimuli in the absence of presynaptic elements
(324). These observations are indicative of the input specificity of LTD in PCs, but according to the recent studies
introduced below, the input specificity of LTD does not
strictly hold for those synapses located within ⬃100 ␮m
from stimulated GA-PC synapses.
When conjunctive LTD was induced by stimulating a
PF beam, test stimulation of a second PF beam at a
distance of 36 –109 ␮m from the first beam revealed
spread of LTD to neighboring synapses despite the fact
that they were not involved in the conjunctive stimulation
(445). The spread still occurred even when the stimulation of the first PF beam was lowered to involve only ⬃20
PF fibers. Spread of LTD to neighboring synapses has also
been demonstrated by locally applying glutamate to PC
dendrites (539). Glutamate was released by uncaging with
3- to 5-␮m diameter ultraviolet (UV) light spot. It was thus
found that glutamate sensitivity of a PC dendrite was
reduced for 100 ␮m from the activated synapses. The
spread of LTD could be mediated by a chemical signal
moving from the conjunctively activated synapses to their
neighborhood, either extracellularly or intradendritically.
Such a signal may be provided by one of the complex
signal transduction processes underlying LTD such as
nitric oxide (NO) (see sect. IIIA2). Functional implication
of the reduced input specificity of conjunctive LTD is
discussed in section VC2.
3. Reduced forms of LTD
In the cerebellum in vivo, iontophoresis of glutamate
or quisqualate, but not kainate or aspartate, to PCs, replacing GA stimulation, effectively induced a persistent
reduction in sensitivity of PCs to glutamate, when combined with CF stimulation (241, 256). In cerebellar slices,
replacement of CF stimuli by application of depolarizing
pulses, which cause the entry of Ca2⫹ into PCs through
voltage-gated channels, induced LTD when combined
with GA stimulation (GA/depolarization-pairing at 1 Hz
for 15 min) (104, 105). To obtain LTD with GA/depolarization-pairing, however, GA stimuli stronger than with
GA/CF conjunction are required, suggesting an additional
contribution of CF stimulation to Ca2⫹ entry (445). A
protocol using 20 pairs of a brief GA tetanus combined
with a subsequent 100-ms depolarization is also effective
in inducing LTD (151).
Various chemical stimuli, related to signal transduction for LTD as reviewed in sections III and IV, induce LTD
when combined with GA stimulation. For example, NO
donors (484), membrane-soluble cGMP analogs (485), and
protein phosphatase inhibitors (12) are effective. The simplest procedure for inducing LTD is to apply quisqualate
(574) or to increase the extracellular K⫹ concentration
(101). The grease-gap method was used for determining
the chemical sensitivity of PCs in a cerebellar slice
trimmed into a wedgelike form (39, 235, 236, 237, 574).
Persistent reduction in AMPA-induced potentials of PCs
was induced by AMPA application following perfusion
of 8-bromo-cGMP, trans-1-aminocyclopentyl-1,3-dicarboxylate (trans-ACPD), a mGluR agonist, or sodium nitroprusside, a NO donor (236).
In cultured PCs devoid of both GAs and CFs, a reduced form of LTD is induced by a combination of glutamate (or quisqualate) pulses and membrane depolarization (328, 329) (Fig. 4B). The LTD then is detected as a
reduced sensitivity of PCs to glutamate or AMPA. This
form of LTD occurs in very simplified preparations devoid
of dendritic spines, indicating that LTD induction does
not require such morphological specialization (407). In
PCs cocultured with granule cells, mEPSCs can also show
LTD (395) (Fig. 4C).
4. Time course
GA/CF-induced LTD in cerebellar slices usually develops progressively over an hour (265, 267) (Fig. 3). In
contrast, glutamate/depolarization-induced LTD in cultured (322) or freshly isolated (407) PCs or GA/depolarization-induced LTD in PCs cocultured with granule cells
(542) reaches a steady peak within a few minutes (Fig.
4B). LTD in cultured PCs occurs in two phases. The
short-term depression (STD) declines after the peak at ⬃5
min and recovers in 30 min and normally is replaced by
the late-phase depression. Inhibitors of phospholipase
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2. Input specificity
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was detected after eye-blink conditioning, even after 1 mo
(467). This learning-specific excitability increase was presumably caused by changes in a K⫹ current, possibly
mediated by an IA-like current, but its relationship to LTD
is presently unclear.
III. SIGNAL TRANSDUCTION:
INITIAL PROCESSES
Section III deals with the initial steps of signal transduction for LTD involving first messengers, receptors, ion
channels, G proteins, and phospholipases. Readers may
also refer to recent review articles (53, 110, 312, 327).
A. First Messengers
In addition to glutamate that plays a major transmitter role in GA-PC synapses and probably also in CF-PC
synapses, NO, corticotropin-releasing factor (CRF), and
insulin-like growth factor I (IGF-I) are released from GAs
or CFs and act on PCs as first messengers (Fig. 5).
1. GA-released glutamate
GAs contain and, upon stimulation, release glutamate
(see Ref. 227). Because the specific antagonist for AMPA-
FIG. 5. Signal transduction underlying LTD. The contents of sections III and
IV are summarized. AMPAR, AMPA receptor; AAR, yet-unidentified amino acid
receptor; ADA, arachidonic acid; ␦2R, ␦2receptor; G-S, G-substrate; IEG, immediate early gene; RyR, ryanodine receptor.
Other abbreviations are defined in the
text. Broken lines indicate suggested, but
not proven, relationships. [Modified from
Ito (232).]
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(PL) A2 (see sect. IIIE2) abolished only the late phase and
left the STD in isolation (322). Apparently, STD is lacking
in GA/CF-induced LTD, which would correspond to the
late phase of glutamate/depolarization-induced LTD. STD
might arise from the use of large depolarizations to replace CF stimuli.
The observation time for LTD in cerebellar slices and
in the cerebellum in vivo is usually 30 min to 1 h, and
occasionally for 2–3 h. In certain special cases, longer
times have been reported. The quisqualate-induced persistent reduction in AMPA sensitivity of PCs, as revealed
by the grease-gap method, was monitored for 12 h without
recovery (235). The amplitude of mEPSCs in cultured PCs
was persistently reduced after 5-min conjunctive application of 50 mM K⫹ and 100 ␮M glutamate, and this reduction lasted for 36 h and recovered to the original level
after 48 h (395) (Fig. 4D). When the hemispheric area of
the lobule simplex (HVI) of rabbit cerebellum was sliced
24 h after the rabbit had been trained for eye-blink conditioning, sequentially applied GA and CF stimuli failed to
induce LTD, which occurred in slices dissected from control rabbits (469). This suggests that LTD underlying the
eye-blink conditioning (sect. VIB2) persists for at least
24 h and precludes eliciting another LTD. An increased
excitability of the PC dendrites in the rabbit lobule HVI
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2. GA-released NO
Nitric oxide synthase (NOS) is of three types: neuronal (nNOS), epithelial (eNOS), and inducible (iNOS). The
nNOS is abundant in the granule cells of the cerebellum
(289, 291, 450); eNOS is also expressed in the granule cells
at a lesser level (125). NOS immunoreactivity is also
strong in basket cells, but not observed in PCs (141). The
mRNAs harvested from single neurons using micropipettes encoded NOS from granule cells, which were absent in PCs (101). Nicotinamide adenine dinucleotide
phosphate diaphorase (NADPH-d), which is a critical coenzyme of NOS, is abundant in the granular and molecular
layers but not in PCs (494, 562). The molecular structure
of nNOS, which is abundant in the brain, contains recognition sites for NADPH and calmodulin, as well as phosphorylation sites resembling those of cytochrome P-450
reductase (68). In cerebellar slices, NO is released by
activation of GAs (483). The NO release from GAs is
potentiated by the tetanic GA stimulation, as well as by
activation of PKA in GAs (283).
The earlier assumption that NO might be released
from CFs, or within PCs stimulated by CF signals, was
based on the following observations. Rats treated with
3-acetylpyridine (3-AP) to lesion CFs showed a substantial reduction in electrical stimulus-induced NO release
(484) or a K⫹-induced increase in cGMP concentration
presumably caused via NO activation of guanylyl cyclase
(sect. IIIB5) (494) in cerebellar slices. These effects are,
however, transient and are not directly related to the loss
of CFs; the cGMP levels in the rat cerebellum were depressed once with a peak on day 7 and thereafter re-
turned to the control level in 14 –20 days (421; see also
Ref. 382).
There is substantial evidence showing that NO plays
a role in LTD induction. 1) Bath application of a NO
donor, sodium nitroprusside (484), or its infusion into PCs
(109), effectively induced LTD. 2) The release of NO from
its caged form within PCs induced LTD when combined
with depolarization-induced Ca2⫹ entry (314). 3) Bath
application of NOS inhibitors readily blocked LTD (103,
484). As would be expected from the location of NOS in
GAs, the postsynaptic application of a NOS inhibitor did
not block LTD (109). 4) Targeted disruption of the nNOS
gene in mice resulted in the virtual loss of NOS activity in
the cerebellum (217), and accordingly, GA/depolarizationconjunction did not induce LTD in cerebellar slices obtained from these mice (316). Photolytic uncaging of NO
and cGMP inside PCs did not recover the loss of LTD,
suggesting that prolonged absence of nNOS might lead to
alteration of the signaling pathway downstream of cGMP.
Thus the requirement of NO in LTD induction in cerebellar slices is evident, but it is to be noted that this is not the
case in cultured PCs. NOS donors, scavengers, or inhibitors did not affect the reduced form of glutamate/depolarization-induced LTD in cultured PCs (326), and LTD in
cultured PCs derived from nNOS-deficient mice was indistinguishable from that in cultures from wild-type mice
(328).
In cerebellar tissues, sensitivity of NOS to Ca2⫹ is
regulated by protein kinase C (PKC) (418). The compound
6R9 –5,6,7,8-tetrahydro-L-biopterin (H4B), a cofactor of
NOS, binds to NOS to stabilize it against phosphorylation
by PKC (420). Cerebellar tissues from those mice partially
deficient in H4B had significantly lower cGMP levels compared with the control (66). Yet, the increase in cGMP
levels following application of a NO donor was normal,
suggesting that impairment of cGMP synthesis in H4Bdeficient mice was due to decreased NO synthesis (see
sect. IIIB5).
The compound NO is unique compared with the
usual neurotransmitters, for it is a short-lived gas diffusing into the vicinity of its source. Calculations based on
the diffusion constant suggest that NO diffuses over 14
␮m in 10 ms (539). Since 1 ␮l of the molecular layer
contains 7.24 ⫻ 108 dendritic spines of PCs (406), a spherical space of the molecular layer, 14 ␮m in radius, would
contain 4,136 spine synapses. Hence, NO released from
one site in the molecular layer would influence 4,000
spine synapse by diffusion of NO in 10 ms. The mediator
for heterosynaptic LTD is yet to be identified, but NO
could be a candidate for it (445).
3. CF-released amino acid
Aspartate and homocysteate were previously proposed as candidate transmitters released from CFs on the
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selective glutamate receptors, 6-cyano-7-nitroquinoxaline2,3-dione (CNQX), blocks GA-PC transmission (298, 429),
glutamate has been established as a transmitter from GAs.
Release of glutamate from GAs in GA-PC transmission is
controlled by Ca2⫹ entering PFs via multiple types of
Ca2⫹ channels (377). Release of glutamate from GAs is
also regulated by mGluR4s, CBR1s (sect. IIB1) and adenosine receptors coupled with adenylyl cyclase, cAMP, and
protein kinase A (PKA) (sect. IVC5).
Glutamate transporters take up the glutamate released into the synaptic gap. Among the five structurally
distinct types of glutamate transporters so far identified,
EAAT4 is abundantly expressed in PCs and is concentrated on the extrajunctional membrane of dendritic
spines in contact with the GAs (510). GLAST, on the other
hand, is highly expressed in the Bergman glial processes
that ensheath GAs to PC synapses (308). Since the time
courses of GA-evoked EPSCs in PCs are normal in both
GLAST-deficient (548) and EAAT4-deficient (512) mutant
mice, these transporters do not appear to be the primary
factors determining the kinetics of GA-evoked EPSPs.
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4. CF-released CRF
CRF-like immunoreactivity has been observed in all
divisions of the inferior olivary nucleus and at all levels,
from the cells of origin of the olivocerebellar afferents in
the inferior olivary neurons to their CF terminals on PCs
(106, 425). A KCl challenge induces CRF release from rat
cerebellar slices (55). CRF plays a permissive role in the
LTD induction in cerebellar slices (sect. IIIB6). However,
because CRF is likely to be absent in tissue cultures
devoid of CFs, CRF may not be an indispensable factor
for the glutamate/depolarization-induced reduced form of
LTD in cultured PCs.
It is noted that besides the CFs, CRF is also distributed densely in the paraventricular nucleus of the hypothalamus, central nucleus of amygdala, and locus coeruleus, all of which are involved in stress responses. The
functional meaning of the presence of CRF in CFs may be
interpreted in connection with the role of CFs in motor
learning (sect. VIA), since motor learning can usually be
accomplished by repeated exhausting exercises. Motor
learning may well be a kind of stress in a wide sense
(238).
5. CF-released IGF-I
IGF-I, a basic peptide, is known to modulate cell
growth and differentiation and to act as a modulator at
diverse synaptic sites. Several lines of evidence indicate
the presence of IGF-I in CFs. The inferior olive exhibits
IGF-I immunoreactivity (4) and expresses IGF-I mRNAs
(59, 551). Electrical stimulation of the inferior olive significantly increased the IGF-I levels in the cerebellar cortex (81). Chemical and surgical lesions of the olivocortical
pathway produced a drastic decrease in cerebellar IGF-I
levels (523). IGF-I antisense oligonucleotide injected into
the inferior olive induced a significant reduction in the
size of dendritic spines on PCs (412). There is now evidence that IGF-I plays a roles in LTD induction (sect.
IIIB7). PCs have been reported to exhibit strong IGF-I
immunoreactivity in the PC cell somata, dendrites, dendritic spines as well as axons, and in the rough endoplasmic reticulum (3, 4, 481). Relationships of the intracellularly localized IGF-I immunoreactivity to LTD induction
are unclear for the present.
B. Receptors
Activation of the four types of receptors by the first
messengers released from GAs and CFs trigger diverse
signaling processes in the membrane of PCs such as the
activation of ion channels, G proteins, and associated
phospholipases (Fig. 5). In addition, NO released from
GAs diffuses into PCs and reacts with an enzyme. A
unique feature of PCs, distinct from most other neurons
including cerebellar granule cells, is the absence of Nmethyl-D-aspartate (NMDA) receptors. Nevertheless,
adult rat PCs intensely express the mRNAs for the subunit
NR1, and the NR2A mRNA weakly (13). NR2D mRNAs are
expressed in PCs transiently during the first week after
birth. Mouse cerebellum also exhibited NR2A and NR2B
immunoreactivity in PCs (519). These subunits apparently
do not form NMDA receptors in adult PCs.
1. AMPA receptor in GA-PC synapses
AMPA receptors mediate the fast GA-PC transmission and are the final target of the signal transduction for
LTD (sect. IVE). AMPA receptors in mature PCs include
mainly GluR2 and GluR3 and also GluR1 subunits (465).
The mRNAs harvested from individual PCs encode the
following five subunits: the flip and flop versions of GluR1
and GluR2 as well as GluR3 flip, with GluR2 being the
most abundant (304). Receptors labeled with antibodies
against GluR2/3 or GluR2 are localized in the synaptic
zone of dendritic spines, with a decrease in receptor
density in the outer 20% of the synapse (431). GluR1 is
also present in the postsynaptic membrane of GA-PC
synapses (43).
Activation of AMPA receptors appears to be one of
the requirements for LTD induction, because the combination of GA/Ca2⫹ spikes failed to induce LTD when
applied in the presence of CNQX (198). Nevertheless,
because LTD can be induced without stimulating AMPA
receptors in cases such as conjunctive activation of
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basis of the results of uptake and release experiments
(534, 555), but only weak immunoreactivity to either aspartate or homocysteate was found in CFs (577). On the
other hand, evidence suggests that glutamate is a transmitter from CFs. 1) CFs exhibit glutamate-like immunoreactivity at a significant level (577). 2) CF-PC transmission is effectively blocked by AMPA-specific antagonists
such as CNQX (298). However, caution is needed because
the excitatory action of homocysteate is also blocked by
CNQX (572), and PCs express distinct aspartate receptors
sensitive to glutamate antagonists (573). 3) Blocking glutamate transporters in PCs by infusion with D-aspartate
through a whole cell clamp micropipette prolonged the
decay of CF-evoked EPSPs (506). Because CF-EPSPs are
normal in EAAT4-deficient mice, another transporter may
be responsible for this effect (512). 4) A transmitter released from CFs activates both AMPA receptors and glutamate transporters expressed by the Bergman glial cells
(130). Interestingly, CF transmitter at the same time presynaptically inhibited GABA-mediated inhibitory synapses on PCs (463).
Despite these lines of supportive evidence, the possibility of glutamate being a CF transmitter remains to be
confirmed since the specific release of glutamate from
CFs has not been proven.
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mGluR with membrane depolarization (108, 198) (sect.
IIIB3), activation of AMPA receptors may not be an indispensable requirement for LTD induction.
Although AMPA receptors are typical ionotropic receptors associated with ion channels, evidence has been
presented that AMPA receptors are also associated with
chemical signal transduction like the metabotropic receptors. The GluR1 subunit in AMPA receptors of cortical
neurons is associated with Gi protein (541). Activation of
AMPA receptors in cerebellar neurons results in activation of protein tyrosine kinase (PTKs) (193), which also
has a role in LTD induction (sect. IVC3).
The ␦2-subtype of glutamate receptors is selectively
expressed in PCs, while low levels of ␦1-subtype are found
widely in the adult brain (22, 344). Immunogold labeling
revealed the presence of ␦1/2-subunits of glutamate receptors in GA-PC synapses with a distribution pattern similar
to AMPA receptors (305, 431). In the dendritic spines of
PCs, ␦-receptors are anchored to actin filaments via spectrin, an actin-binding protein (205, 206).
A role for ␦2-receptors in LTD induction is suggested
by two major findings. 1) Treatment of cultured PCs with
an antisense oligonucleotide against the ␦2-subunit mRNA
blocked LTD induction but had no appreciable effect on
the basic physiological or morphological properties of
PCs (208, 250). 2) PCs in cerebellar slices (269) and tissue
cultures (209) derived from ␦2-deficient gene-knockout
mice did not exhibit LTD.
The ␦2-receptors do not form functional glutamategated ion channels. However, when an A (alanine)-to-T
(threonine) point mutation is introduced at position 654,
the end of its third transmembrane segment, as occurs in
lurcher mutant mice, and when a Q (glutamine)-to-R (arginine) mutation is also induced at the so-called Q/R site
in the second transmembrane segment, the modified homomeric ␦2-receptors display ion channel activity including a moderate Ca2⫹ permeability in the absence of ligand
binding (293). A factor(s) that may activate ␦2-receptors,
a ligand, a receptor subunit or associated messengers
have yet to be found for understanding how ␦2-receptors
contribute to LTD induction.
immunoreactivity for mGluR1a in both somatic and dendritic regions (173, 410). In the mouse cerebellum, 80% of
all PC dendritic spines express mGluR1a immunoreactivity. The expression was retained even when presynaptic
GAs were lost by intoxication with methylazoxy methanol
(504). In the dendritic spines of PCs, both mGluR1a and
mGluR1b are localized in the perisynaptic areas outside
the postsynaptic densities (346, 362, 431). While mGluR1a
dominates within 60 nm from the edge of the postsynaptic
densities, mGluR1b distributes more evenly to over 360
nm (362).
The involvement of mGluR1 in LTD induction has
been demonstrated in the following experiments. 1) LTD
induction in cerebellar slices was blocked by an antagonist of mGluR1, (RS)-a-methyl-4-carboxyphenylglycine
(MCPG) (185). 2) Antibodies inactivating mGluR1
blocked the reduced form of LTD in cultured PCs (487).
3) LTD was impaired in mGluR1-deficient gene-knockout
mice (6, 100). The transgenic mice whose mGluRs were
rescued only in the cerebellum restored normal LTD
(220). 4) Activation of mGluRs by the agonists transACPD or 1S,3R-aminocyclopentyl-dicarboxylate (1S,3RACPD) induced LTD when combined with GA tetanus
(102) or depolarization-evoked Ca2⫹ spikes, even in the
presence of CNQX (108, 198).
Activation of mGluR1 evokes mGluR-EPSPs in PCs
(39, 40). The mGluR-EPSPs induced by repetitive stimulation of GAs (usually 8 pulses at 50 Hz) have a slow time
course when observed in the presence of an AMPA antagonist (peak time, 200 –300 ms). Even though mechanisms for generating mGluR-EPSPs have not yet been
identified, Tempia et al. (514) suggest that it is due to
activation of a nonspecific cation channel. In fact, generation of mGluR-EPSPs is associated with an increase in
intradendritic Na⫹ concentration (288). An alternative
possibility is the activation of an electrogenic Ca2⫹/Na⫹
exchanger that extrudes Ca2⫹ released from intracellular
stores by the activation of mGluR1s (sect. IVA2). However, because KB-R7943, a selective inhibitor of the Ca2⫹/
Na⫹ exchanger, only partially depressed the mGluR agonist-evoked inward currents, mGluR-EPSPs may have
only a minor contribution from the Ca2⫹/Na⫹ exchanger
(210).
3. mGluR in GA-PC synapse
4. Glutamate receptor in CF-PC synapses
Eight subtypes of the mGluR family are classified into
three groups: I (mGluR1 and -5), II (mGluR2 and -3), and
III (mGluR4, -6, -7, -8) (98, 401). Group I subtypes are
characterized by their stimulating phosphatidylinositol
hydrolysis and Ca2⫹ release from intracellular stores,
whereas the group II and III subtypes negatively regulate
cAMP formation. Several of these subtypes have multiple
splice variants. So far, four isoforms of mGluR1 (a-d) have
been detected in PCs (49, 177). Cultured PCs exhibit
In CF-PC synapses, all three subunits of the AMPA
receptors (GluR2, GluR3, GluR1) and mGluR1 are distributed in a similar manner to GA-PC synapses (43). The
␦2-receptors are expressed in both GA-PC and CF-PC
synapses during developmental stages, but after postnatal
day 21 and in adulthood, ␦2-receptors are scarce in CF-PC
synapses, while they are predominant in GA-PC synapses
(579, 431). The report that L-homocysteinic acid generates
substantial responses in cultured PCs (572) may draw
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2. ␦2-Receptor in GA-PC synapses
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CEREBELLAR LONG-TERM DEPRESSION
thesis (347, 419). Another potent activator of guanylyl
cyclase is arachidonic acid (524) (sect. IVB5).
6. CRF receptor
The CRF type 1 receptor (CRFR1) and its mRNAs are
present on the somata and dendrites of PCs (437). CRFR1
is positively coupled with adenylyl cyclase through Gs
proteins (42), but there is no evidence indicating that
adenylyl cyclase, cAMP, or PKA has any role in LTD
induction (sect. IVC5). There is evidence that PKC is activated via CRF receptors in cerebellar tissues (382).
Involvement of CRFR1s in LTD induction is indicated
by the finding that CRF antagonists, ␣-h CRF and astressin, blocked LTD induction (382). For LTD induction,
however, CRF release driven by CF impulses does not
appear to be required each time because the CRF antagonists effectively block the LTD induced by GA/Ca2⫹
spike conjunction without stimulating CFs. CRF released
spontaneously from CF may play a permissive role in LTD
induction.
7. IGF-I receptors
5. Guanylyl cyclase
The soluble form of guanylyl cyclase is a heme-containing protein involved in the enzymatic conversion of
GTP to cGMP. Soluble guanylyl cyclase is localized in
PCs, particularly in the primary dendrites (27), and the
mRNA for soluble guanylyl cyclase is expressed in the
granule cells and PCs (543). Soluble guanylyl cyclase acts
as a receptor for NO and, in the NO-activated form, synthesizes cGMP. In cultured PCs, immunofluorescence associated with a monoclonal antibody recognizing both ␣and ␤-subunits of soluble guanylyl cyclase was shown to
increase in response to NO generated by a NO donor
(525). Intracellular application of the potent and selective
inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazole[4,3-a] uinoxalin-1-one (ODQ), has been shown to
effectively block LTD induction (62).
Carbon monoxide (CO) is an activator of guanylyl
cyclase and is formed by the catalytic action of inducible
type 1 and constitutive type 2 heme oxygenase. The heme
oxygenase-2 mRNA is densely distributed in the granular
cells and PCs, similarly to the mRNA for soluble guanylyl
cyclase, which may suggest that CO replaces NO in activating soluble guanylyl cyclase (533). Nevertheless, this
possibility is doubtful because of the low enzymatic activity of the soluble guanylyl cyclase-CO complex (212). In
primary cultures of olfactory neurons, zinc-protoporphyrin-9 (ZnPP), a heme oxygenase inhibitor, was shown to
deplete endogenous cGMP (533). However, the specificity
of ZnPP to heme oxygenase is questionable because ZnPP
may act directly on soluble guanylyl cyclase or may deplete intracellular L-arginine that is required for NO syn-
PCs express receptors for IGF-I (60, 162, 551). Involvement of IGF-I in LTD induction has been suggested
in a microdialysis experiment where glutamate applied to
rat cerebellar cortex induced the release of GABA from
the cerebellar nucleus (82). The glutamate-induced GABA
release was persistently inhibited when IGF-I, but not the
basic fibroblast growth factor (bFGF), was also applied to
the cerebellar cortex (81). Electrical stimulation of the
inferior olive in conjunction with glutamate application to
the cortex also inhibited subsequent glutamate-induced
GABA release from the nuclei. A PKC inhibitor and a NOS
inhibitor blocked the effect of glutamate/IGF-I conjunction in depressing the glutamate-induced GABA release. A
phorbol ester, a PKC activator, or L-arginine, a NO donor,
when applied in conjunction with glutamate, mimicked
the effect of IGF-I in depressing the GABA release.
More direct evidence for the involvement of IGF-I
and its receptors in LTD induction has recently been
reported (542). Application of IGF-I or insulin that also
binds to IGF-I receptors effectively induced LTD in cultured PCs as represented by a reduction of AMPA currents, but not NMDA currents, and this effect of IGF-I was
blocked by an antibody or an inhibitor of IGF-I receptors.
How the activation of IGF-I receptors results in LTD
induction is not clear for the present. Because IGF-I stimulates production of 1,2-diacylglycerol (DAG) (295), it
could in turn activate PKC as required for LTD induction
(sect. IV, B1 and C1). Because partial peptides of dynamin
and amphiphysin that interfere with endocytosis blocked
the IGF-I-induced LTD (541), this form of LTD may be
caused by internalization of AMPA receptors by endocytosis, as suggested to occur in the final stage of signal
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attention because of the earlier proposal that L-homocysteate might be a transmitter (sect. IIIA3), but these
responses are mediated by AMPA receptors.
Receptors in CF-PC synapses are blocked by CNQX
(29) similarly to AMPA receptors in GA-PC synapses
(290). However, these two types of synapses differ in their
sensitivity to another antagonist, a synthetic analog of
Joro spider toxin, 1-naphthyl-acetyl-spermine (NAS). NAS
blocked the GA-PC synapses in cerebellar slices but not
the CF-PC synapses (11). It is noted that, in cultured
hippocampal neurons, NAS differentially blocked AMPA
receptors associated with a strong inward rectification
and permeability to Ca2⫹, but not those associated with a
slight outward rectification and low Ca2⫹ permeability
(294). In recombinant glutamate receptors expressed in
Xenopus oocytes, NAS differentially blocked AMPA receptors composed of GluR1, GluR3, GluR4, or GluR1/3,
but not those composed of GluR1/2, GluR2/3, or GluR6
(56). These results would suggest that the AMPA-type
receptors in the CF-PC synapses may have a different
subunit composition from those in GA-PC synapses.
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transduction for LTD (sect. IVE3). Insulin-induced LTD
also reduced the number of GluR2-containing AMPA receptors in tissue-cultured hippocampal neurons, and this
form of LTD is caused by clathrin-dependent endocytosis
(356).
C. Ion Channels
Ions enter neurons in general through voltage-sensitive as well as ligand-gated channels. Synaptic transmission in GA-PC and CF-PC synapses induces movement of
ions across PC membrane.
Because PCs do not develop NMDA receptors associated with Ca2⫹ channels (see above), Ca2⫹ entry to PCs
is mostly mediated by voltage-sensitive Ca2⫹ channels,
occurring during either Ca2⫹ spikes or current-induced
membrane depolarization (315, 373, 377, 513). A significant transient entry of Ca2⫹ in PC dendrites occurs during
Ca2⫹ spikes and associated plateau potentials, but some
Ca2⫹ signals also occur in somata (263, 315, 373). Ca2⫹
entry is induced not only during CF-evoked Ca2⫹ spikes,
but also during AMPA-EPSPs induced by GA stimulation
of below the threshold of the generation of Ca2⫹ spikes.
This Ca2⫹ entry is confined to a compartment consisting
of a small number of branchlets of terminal spiny dendrites (142) or even in individual dendritic spines (112).
The dendritic Ca2⫹ signals depended on the size of GAevoked EPSPs so that 20 –30 GAs must be activated
within the local dendritic area to produce a detectable
increase in the postsynaptic Ca2⫹ concentration. Ca2⫹
entry is indispensable for LTD induction (sect. IVA1).
Six types of voltage-dependent Ca2⫹ channels have
so far been identified (termed T, L, N, P, Q, and R). These
channels are heteromultimeric complexes composed minimally of one main subunit, ␣1, serving as both pore and
voltage sensor, and auxilliary ␤- and ␣2␦-subunits. PCs are
immunoreactive to ␣1A in the somata as well as the entire
length of dendrites (553). The high-threshold P channel
was originally described in PCs (339). The high-threshold
Q channels were first described in cerebellar granule cells
as distinct from P channels in its inactivation kinetics and
sensitivity to ␻-agatoxin IVA, a spider toxin (442). P and Q
channels appear to be generated by alternative splicing of
the ␣1A-subunit gene (61). The funnel web spider toxin
(FTX), a specific P channel blocker, abolished the Ca2⫹
spikes in PCs (529). The ␻-agatoxin IVA, which blocks Q
type of Ca2⫹ channels, abolished the depolarization-induced Ca2⫹ spikes, the spike-associated steep increase in
the dendritic [Ca2⫹]i, and the steady intrasomatic increase
in Ca2⫹ concentration (546). Thus P/Q channels are responsible for the generation of dendritic Ca2⫹ spikes. The
N and L types of high-voltage-activated Ca2⫹ channels are
also expressed in PC dendrites (552), but evidence supporting the possibility that N or L types of Ca2⫹ channels
play significant roles in PC functions is limited (546).
The presence of low-voltage-activated (also called
low-threshold or T type) Ca2⫹ channels has been controversial. The results of electrophysiological recordings and
optical Ca2⫹ measurements suggest the presence of the T
type of Ca2⫹ channels in the PC dendrites (392, 546). Of
the three T-channel-related ␣1-subunit genes (␣1G, ␣1H,
and ␣1l), ␣1G-mRNAs were found to be strongly expressed
in PCs (509). The ␣1E-subunit of another low-voltage-activated/fast-inactivating type of Ca2⫹ channel was also reported to be present in the fine dendrites of PCs (571).
The blockade of low-voltage-activated Ca2⫹ channels by
Ni2⫹ delayed the onset of generation of depolarizationinduced Ca2⫹ spikes, suggesting that the T-type Ca2⫹
channels or those containing the ␣1E-subunit generate
transient inward currents that facilitate the generation of
Ca2⫹ spikes (546).
2. Na⫹ and K⫹ channels
Na⫹ enters PCs via glutamate-gated cation channels,
voltage-sensitive Na⫹ channels, and Ca2⫹/Na⫹ exchangers. An increase in [Na⫹]i was observed in both dendrites
and somata after GA stimulation (77). However, the increase in the somatic [Na⫹]i was observed only when
regenerative spikes were detected in the somata and
therefore would represent Na⫹ entry through voltagesensitive Na⫹ channels. The increase in the dendritic
[Na⫹]i evoked by GA stimulation was blocked by CNQX
and should be associated with AMPA receptors.
In cultured PCs, multiple types of voltage-sensitive
K⫹ channels having different single-channel conductances have been identified in both PC somata and dendrites (180). An excitability increase in PC dendrites,
presumably due to changes in a K⫹ current, has been
detected even 1 mo after eye-blink conditioning (468).
D. G Proteins
Guanine nucleotide-binding G proteins are coupled
with a variety of metabotropic receptors. Activation of
metabotropic receptors results in conversion of the inactive form of G protein coupled with GDP to its active form
coupled with GTP. Because the G protein itself is a GTPase, the active form of G protein coupled with GTP will be
ultimately converted back to its inactive form coupled
with GDP. In the heterotrimeric structure of G proteins,
␤␥-subunits are bound to an ␣-subunit maintaining it in a
low-activity state. When metabotropic receptors are activated, ␤␥-subunits are released leaving the activity of the
␣-subunit high.
There are ⬃20 different species of G proteins exerting different effector actions. Gs is a family of G proteins
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1. Ca2⫹ channels
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E. Phospholipases
1. PLC
PLC is a family of enzymes that hydrolyze the membrane phosphatidylinositol 4,5-bisphosphate (PIP2) producing two second messengers: DAG (see sect. IIID1) and
inositol trisphosphate (IP3, see sect. IIID2). Among its five
isoforms of ␣, ␤, ␥, ␦, and ⑀, three (␤, ␥, and ␦) are
phosphoinositide specific, and PLC-␤ alone is associated
with G proteins (199). The activation of metabotropic
receptors leads to the activation of PLC-␤ via the activation of Gq/11. The four isoforms of PLC-␤ have recently
been cloned, of which PLC-␤3 mRNA is specifically expressed in PCs, and PLC-␤4 mRNA is most highly expressed in PCs, whereas PLC-␤1 and -2 are localized in
other areas of mouse and rat brain (456, 545). PLC-␤4 is
distributed equally in both the rostral and caudal cerebellum, whereas PLC-␤3 is abundant in the caudal compared
with the rostral cerebellum. In other words, PLC-␤4 functions dominantly in the rostral cerebellum, while PLC-␤3
and PLC-␤4 function to a similar extent in the caudal
cerebellum. In PLC-␤4-deficient mice, the activation of
mGluR1s, which normally induces an increase of [Ca2⫹]i
in the cerebellum, resulted in no such effect in the rostral
cerebellum and only a small increase in the caudal cerebellum (501). PLC-␤3 and PLC-␤4 are activated differently
from each other by subunits of Gq proteins (199, 248);
␣-subunit activates PLC-␤4 more potently than PLC-␤3,
whereas ␤␥-subunit is much more effective in activating
PLC-␤3 than PLC-␤4 (501).
The PLC-mediated pathway, presumably involving
Gq/11 and PLC-␤3/4, plays a crucial role in LTD induction,
since its downstream effects, both activation of PKC by
DAG and release of Ca2⫹ from intracellular stores by IP3,
are required for LTD induction (sect. III, B1 and B2). A
PLC inhibitor actually greatly attenuated the mGluR agonist-induced [Ca2⫹]i increase (410), which was also
blocked in mice deficient in the PLC-␤4 gene (264). On the
other hand, PLC does not seem to contribute significantly
to the generation of mGluR-EPSPs because PLC inhibitors, PKC inhibitory peptides, or heparin sodium, a nonspecific inhibitor of IP3 receptors, have no significant
effects on the mGluR-EPSPs (514) or mGluR agonistinduced inward currents (210). This is consistent with the
report that photolytic release of IP3 from its caged form
did not induce an inward current (501).
2. PLA2
PLA2 is a superfamily of enzymes that hydrolyzes
ester bonds of the membrane phospholipids, thereby releasing unsaturated free fatty acids such as arachidonic
and oleic acids on one hand and lysophosphatidylcholine
on the other. Platelet-activating factor (PAF) is also a
product of PLA2 activity (sect. IIIE2). PLA2 is classified
into two distinct forms: secreted and cytosolic (cPLA2).
cPLA2 is rapidly activated by increased concentrations of
cytosolic Ca2⫹, which cause the translocation of cPLA2
from the cytosol to membranes. The 85-kDa cPLA2
(cPLA2␣) is widely distributed in the central nervous
system. In the cerebellum, its mRNAs are abundant in the
granular and PC layers including the PC cytoplasms, but
only moderately contained in the molecular layer (285).
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that activates adenylyl cyclase, whereas Gi inhibits adenylyl cyclase or activates cGMP-phosphodiesterase. A new
class of G proteins, the Gq family, has recently been
identified and found to be associated with group I mGluRs
(sect. IIIB3) and involved in PLC activation (sect. IIIC4). Of
the four isoforms of G␣q subunits (G␣q, G␣11, G␣14, G␣15/16),
the highest transcriptional rate of G␣q was observed in
PCs and hippocampal pyramidal cells. That of G␣11 was
also noted in hippocampal pyramidal cells, but the other
two were scarce in the central nervous system (511). The
isoforms G␣q and G␣11 share a similar amino acid sequence (88%), receptor specificity, and ability to activate
PLC-␤. Immunoreactivity for an antibody against the
COOH terminus common to G␣q and G␣11 is abundant in
the dendrites of PCs (352). With immunogold labeling,
G␣q/␣11 immunoparticles are distributed in the perijunctional zones within 600 nm from the edge of the postsynaptic densities, corresponding to the perijunctional distribution demonstrated for mGluR1 (511) (sect. IIIB3).
Certain bacteria toxins are used to disrupt G protein
activities by ADP-ribosylation of the ␣-subunit of G protein (30). Cholera toxin blocks the Gs family, and pertussis toxin blocks the Gi family. The Gq family, however, is
resistant to both of these toxins. The action of mGluR1s
to release Ca2⫹ from intracellular stores in PCs (sect.
IIID2) is insensitive to pertussis toxin (575), as would be
expected because this action is mediated by G␣q protein.
However, quisqualate-induced reduced form of LTD, recorded by the grease-gap method, was blocked by pertussis toxin (236), suggesting the involvement of another
type of G protein, probably Gi, in LTD induction.
Hydrolysis-resistant analogs of GTP such as guanosine 5⬘-O-(2-thiodiphosphate) (GDP␤S) and guanosine
5⬘-O-(3-thiotriphosphate) (GTP␥S) are also used to interfere with G protein activities by persistently activating
effector systems. Photolytic release of GTP␥S in PCs
produces a large inward current followed by a small
outward current, mimicking the response to an mGluR
agonist (1S,3R-ACPD) (sect. IIIB3) (501). On the other
hand, prolonged intracellular infusion of either GDP␤S or
GTP␥S prevented the 1S,3R-ACPD-induced generation of
the inward current (210). In mice deficient in G␣q, CF-PC
and GA-PC transmission was functional, but CFs remained to multiply innervate PCs (414) and LTD was
lacking (381).
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IV. SIGNAL TRANSDUCTION:
FURTHER PROCESSES
After the initial processes of signal transduction described in section III, intracellular ion concentrations are
set high, and a number of second messengers are produced to activate protein kinases and phosphatases.
There are still a number of factors that may contribute to
LTD induction, yet mechanisms of their action have not
yet been well understood. The final process of LTD induction is inactivation of AMPA receptors mediating GA-PC
synapses. Eventually, a complex network of chemical
reactions accounts for signal transduction for LTD.
A. Ion Concentrations
1. Ca2⫹ concentration
During current-induced depolarization from ⫺70 to 0
mV, Ca2⫹ concentration attained 30 ␮M in PC dendrites
and 5 ␮M in PC somata on the average of a number of
measurements (349). Two lines of observations have demonstrated the requirement of Ca2⫹ for LTD induction: 1)
LTD induction was blocked after intracellular injection of
Ca2⫹ chelators, such as EGTA (460, 151) or BAPTA (297);
and 2) activation of Ca2⫹ channels by current step-elicited
membrane depolarization induced LTD when combined
with GA stimulation (104, 297). Membrane depolarization
by itself is not a factor required for LTD induction, because an increase in [Ca2⫹]i caused by photolysis of nitr 5,
a photolabile Ca2⫹ chelator, effectively induced LTD
when combined with the iontophoretic application of glutamate in cultured PCs (270). When the GA-evoked Ca2⫹
entry is sufficiently large, it can replace the CF-evoked
Ca2⫹ spikes so that GA stimulation alone can induce
homosynaptic LTD (188, sect. VC1).
[Ca2⫹]i is regulated by buffering by Ca2⫹ binding
proteins and diffusion. PCs contain three types of endogenous Ca2⫹ binding proteins, namely, calbindin-D28K,
parvalbumin, and calrectin (556). All PCs in various animal species display strong immunoreactivity to calbindinD28k. All PCs in chicks and rats (451, 452) also display
immunoreactivity to parvalbumin, but in monkeys, a significant portion of parvalbumin-negative PCs occur
among the positive PCs (149). PCs in chicks and rats
show no immunoreactivity to calrectin, or its mRNAs, but
in monkeys about half of PCs display weak calrectin
immunoreactivity, and in humans, calrectin immunoreactivity appears in PCs after 21 wk of gestation and increases thereafter (570). In rat cerebellum, calrectin immunoreactivity appeared in PFs and their varicosities that
formed synapses with unlabeled PC dendriticc spines,
suggesting a role of calrectin at the presynaptic sites of
GA-PC synapses (21). Mice deficient of calbindin-D28k, or
both calbindin-D28k and parvalbumin, exhibited abnormal morphology of dendritic spines of PCs (532). Calbindin-D28k null mutant showed motor discoordination,
and their PCs displayed marked changes of synaptically
evoked postsynaptic Ca2⫹ transients, their fast decay
component having larger amplitudes in null mutant than
in wild-type mice (7). The existence of two types of Ca2⫹
buffer in cultured PCs has recently been revealed: a highaffinity, cooperative, and mobile Ca2⫹ buffer, resembling
calbindin-D28k, and a immobile, low-affinity Ca2⫹ buffer
(349).
2. Na⫹ concentration
An important role of Na⫹ in inducing LTD was suggested in an experiment using cultured PCs. The quisqual-
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Of the other two novel types of cPLA2, i.e., cPLA2␤ (114
kDa) and cPLA2␥ (61 kDa), cPLA2␤ is most strongly expressed in the cerebellum compared with other parts of
the central nervous system and various organs (433). The
PLA2 immunostained in the PC somata and dendrites had
a molecular mass slightly above 100 kDa (271) and may be
equivalent to cPLA2␤.
The involvement of PLA2 in LTD induction was
shown in cultured PCs, in which inhibitors of PLA2, manoalide and mepacrine (equivalent to quinacrine), blocked
the late phase of glutamate/depolarization-induced LTD
(322). The role of PLA2 in LTD induction may be considered in connection with its link to type 1 mGluRs, which
plays a role in the LTD induction (sect. IIIB3). This link is
apparent because stimulation of mGluRs causes a release
of arachidonic acid, a product of PLA2, from neurons (23,
129, 343). A PLA2 activating protein (PLAP) is known to
intercalate signal transduction from mGluRs to PLA2. A
30-kDa PLAP isolated from Aplysia ganglia is also located
in rat cerebral cortex and is activated by PKC (75). In
addition to the above postulated mGluR-G protein-PLA2
pathway, a possibility has also been raised that cPLA2 is
activated by mitogen-activated protein kinases (MAPKs)
by phosphorylation at serine-505 (320) (sect. IVC). PLA2 is
also activated by PKC (99), but this is probably mediated
through activation of MAPK by PKC (320).
mGluRs are thus linked to LTD induction via both the
PLC pathway involving PKC and IP3 (sect. IV, B2 and C1)
and the PLA2 pathway. PKC may activate PLA2 either
directly or indirectly via activation of MAPK. Arachidonic
acid, a PLA2 product, is known to exert a long-lasting
activation on PKC-␥, but not PKC-␣ or -␤ (479) (see sect.
IVC). If PKC involved in LTD induction is ␥-isoform, a
possibility arises that PLC and PLA2 mutually activate and
provide a mechanism of self-regeneration required for the
initial development of synaptic plasticity (see sect. IVF).
However, because PKC-␥-deficient mice retain LTD (2),
this possibility does not seem to be realistic (see sect.
IVC1).
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CEREBELLAR LONG-TERM DEPRESSION
ate/depolarization-induced LTD was blocked by replacing
extracellular Na⫹ with Li⫹, Cs⫹, tetraethylammonium, or
N-methyl-D-glucamine, or by pairing quisqualate pulses
with step depolarizations to near the membrane equilibrium potential of Na⫹, thus preventing Na⫹ entry via Na⫹
channels (330). How Na⫹ influx contributes to LTD induction has not yet been clarified, but it is probable that Na⫹
ions are required for activation of certain enzymes. It is
noted that PCs are equipped with a powerful Na⫹-K⫹ATPase sodium pump, which constantly hyperpolarizes
PC membrane (165). The sodium pump activity and
ouabain binding to cerebellar homogenates in rat increase
with development (385).
After the activation of the receptors and enzymes by
the first messengers and subsequent activation of ion
channels, G proteins and phospholipases as aforementioned, a number of second messengers are produced and
activate various signal transduction cascades (Fig. 5).
According to the general scheme of metabotropic receptor-initiated signal transduction, signals received by
metabotropic receptors are transferred to a target molecule via G proteins and at the same time to one or more
effector molecules that regulate second messengers acting upon the target molecule.
1. DAG
The substance DAG, generated by PLC from membrane PIP2, is a major activator of PKC. DAG has been
assumed to take part in LTD induction by activating PKC
(sect. IVC). Direct evidence for the involvement of DAG in
LTD induction was derived from the observation that
application of exogenous synthetic DAG (oleoylacetylglycerol and dioleoylglycerol) to cultured PCs in combination with depolarizing pulses and test AMPA pulses
induced LTD (408).
DAG is under regulatory influences of DAG kinase
(DGK), which phosphorylates DAG to generate phosphatidic acid. DGK is hence considered to attenuate the PKC
activity. DGK may also initiate the resynthesis of phosphatidylinositols that have been cleaved by PLC. The
phosphatidic acid produced by DGK may well be a second
messenger itself. Nine isoforms of DGK have been identified, and their activity is found not only in the membrane, but also in the nucleus and the cytoskeleton (530).
DGK␥ is predominant in PCs, while DGK␨ distributes in
the cerebral and cerebellar cortices (174). DGK in the
cerebellum and cerebrum is activated by arachidonic acid
(sect. IVB5).
2. IP3
The activation of mGluR1s results in the production
of IP3 via G␣q and PLC-␤. In the cerebellum, this was
previously demonstrated by an increase in phosphoinositide turnover in PCs and the molecular layer following the
activation of mGluR1s by trans-ACPD (219). Serotonin
also stimulated IP3 production in the cerebellum (462).
IP3 5-phosphatase hydrolyzes IP3 to inositol 1,4-bisphosphate (IP2), and IP3 3-kinase phosphorylates IP3 to 1,3,4,5tetrakisphosphate (IP4). In the adult rat cerebellum, IP3
3-kinase activity is comparable to that in the cerebral
cortex and hippocampus, while 5-phosphatase activity is
5- to 10-fold higher than in other parts of the brain (194).
mRNA for type 1 IP3 5-phosphatase is localized in PCs
(115). Immunoreactivity to IP3 3-kinase is strong in the
dendrites (353, 383), particularly in dendritic spines of
PCs and basket cells (560). IP3 3-kinase mRNA is highly
expressed in PCs (354).
Receptors specific to IP3 are abundantly present in
PCs (350). IP3 receptors constitute a family of Ca2⫹ channels involved in mobilization of intracellular Ca2⫹ stores,
of which three different gene products (I-III) have been
isolated (427). Immunoreactivity to IP3 receptors is detected mainly in the endoplasmic reticulum, but not in the
mitochondria or the cell membrane (455). A morphological counterpart of IP3 receptors is small dense projections
observed on the cytoplasmic surface of smooth endoplasic reticulum in PCs, which appear to be composed of
four subparticles, surrounding a central channel (254). IP3
receptors are present in particularly high concentrations
within stacks of the endoplasmic reticulum cisternae,
which may be massively formed as an adaptive response
to the high concentration of IP3 receptors (508). The
intracellular Ca2⫹ stores in the cerebellum appear to consist of the three microsomal components, i.e., IP3 receptors, membrane fragments endowed with Ca2⫹ pumps,
and a calcium-binding protein, calsequestrin (535). It has
recently become apparent that, when intracellular Ca2⫹
stores are depleted, specific store-operated Ca2⫹ channels
in the plasma membrane open to cause capacitative Ca2⫹
entry so as to prevent exhaustion of the intracellular Ca2⫹
(374, 438). It has also been known that IP3 receptors
interact with many cytoskeletal proteins and their modulators and that the sequential process from activation of
mGluR1s to activation of IP3 receptors is facilitated by a
protein called Homer (526) or Cupidin (490), which crosslinks mGluRs with IP3 receptors.
IP3 activates its receptors and thereby opens associated Ca2⫹ channels, leading to the release of Ca2⫹ from
intracellular stores located mainly in the endoplasmic
reticulum. IP4 also releases Ca2⫹ from cerebellar microsomes to a lesser degree than IP3 (251). Repetitive GA
stimulation produced a transient local increase in dendritic [Ca2⫹]i with early and late components. The early
component is associated with AMPA receptors, because
its time course corresponds to the fast EPSPs, and it is
blocked by CNQX. The late component is associated with
mGluR1-IP3-mediated Ca2⫹ signals, because it is blocked
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B. Second Messengers
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MASAO ITO
LTD induction. 3) Exogenous synthetic DAG successfully
induced LTD, even while it activates PKC, but does not
induce Ca2⫹ release from intracellular stores. Mechanisms for maintaining [Ca2⫹]i and their involvemnt in LTD
might be altered in isolated PCs.
3. Ryanodine receptor
Ryanodine receptors provide another Ca2⫹-releasing
mechanism. While several subtypes of ryanodine receptors are present in PCs, the skeletal muscle type (␣-form,
but not ␤-form) of ryanodine receptor is specific to PCs in
the nervous system (302, 423). Ryanodine receptors are
present in the PC somata, dendrites, and axons, but in
contrast to IP3 receptors, they are not found in the dendritic spines (143). Although IP3 receptors are involved in
IP3-induced Ca2⫹ release, ryanodine receptors function as
intracellular channels for Ca2⫹-induced Ca2⫹ release
(182). The transient increase in [Ca2⫹]i in the PC somata
and dendrites after the addition of caffeine is presumably
mediated by ryanodine receptors, since it was blocked by
ruthenium red, a ryanodine receptor inhibitor (257). Cyclic ADP ribose (cADPR) acts on the nonskeletal type of
ryanodine receptor Ca2⫹ channels (371). If the level of
cADPR is regulated by cGMP as observed in sea urchin
eggs (160), it is possible that ryanodine receptors are
activated via the NO-cGMP pathway as part of the signal
transduction for LTD induction (48).
In the GA/CF conjunction, the CF-induced increase in
[Ca2⫹]i in the PC dendrites may be amplified by the Ca2⫹
released from the ryanodine-sensitive Ca2⫹ stores under
the influence of NO released from GAs. The CF-induced
elevation in the levels of Ca2⫹ within the dendrites may
spread into the spine and sensitize IP3 receptors to the IP3
generated via the mGluR1 activation due to GA impulses;
IP3 receptors within the spine may thus function as a
molecular coincidence detector (48). In fact, ryanodine
receptors are likely to have a role in the induction of LTD
by glutamate/depolarization conjunction in cultured PCs,
because ryanodine, which keeps ryanodine receptor-associated Ca2⫹ channels open, and ruthenium red, which
inhibits rynodine receptor, blocked the LTD induction
(292).
4. cGMP
The compound NO activates synthesis of cGMP in
cerebellar neurons (163). The cGMP is produced from
GTP by the catalytic action of guanylyl cyclase (sect.
IIIB5) and is degraded to GMP by phosphodiesterase.
Calmodulin-dependent phosphodiesterase is highly expressed in the PC somata and dendrites (32). Interestingly, degeneration of CFs by a 3-AP treatment resulted in
a selective reduction in phosphodiesterase expression in
PCs, without affecting other calmodulin-binding proteins
in PCs and without changing phosphodiesterase activity
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by MCPG and also by heparin sodium (147, 507). Application of a series of weak stimuli to GAs induced IP3mediated Ca2⫹ signals discretely restricted to individual
dendritic spines, whereas that of stronger stimuli increased Ca2⫹ concentration in dendritic spines as well as,
to a lesser degree, in adjacent dendritic shafts (147, 539).
Ca2⫹ signals induced by photolysis of caged IP3 by a beam
of 3–5 mm in size spread to 12.3 ␮m in a half-width along
the dendritic branchlet (147).
The following observations indicate that the Ca2⫹
thus released are involved in LTD induction. 1) Depletion
of Ca2⫹ from the intracellular stores by thapsigargin, an
inhibitor of Ca2⫹-ATPase on the endoplasmic reticulum,
blocked the induction of mGluR/Ca2⫹ spike-induced LTD
in cerebellar slices (198) and glutamate/depolarizationinduced LTD in tissue cultures (292). However, it is noted
that thapsigargin did not block GA/Ca2⫹-spike induced
LTD (198). LTD induced by using sparse activation of GAs
was blocked by thapsigargin, whereas LTD induced by
dense activation of GAs was insensitive to thapsigargin
(539). This is in accordance with the fact that the sparse
GA stimulation enhances Ca2⫹ signals confined in spines,
while strong GA stimulation induces Ca2⫹ into dendritic
branchets via voltage-sensitive Ca2⫹ channels. 2) Heparin
sodium, an inhibitor of the IP3 receptor, blocked glutamate/depolarization-induced LTD in tissue cultures. 3)
The combination of AMPA application and depolarization,
which alone did not induce LTD, induced LTD when
applied in conjunction with photolysis of caged IP3 (270).
Combination of photolysis of caged IP3 and large depolarizing pulses also induced LTD (280). 4) A specific antibody against the IP3 receptor blocked the LTD induction, and mice with a disrupted IP3 receptor type 1 gene
completely lacked LTD (222). 5) IP3-mediated Ca2⫹ signaling in dendritic spines of PCs, and concomitantly LTD,
were absent in those mice and rats with mutations in
myosin-Va, in which the endoplasmic reticulum failed to
enter the dendritic spines (380). The loss of LTD was
rescued by photolysis of a caged Ca2⫹ compound. 6) In
mGluR1-deficient knockout mice, the photolytic release
of IP3 is sufficient to rescue GA/Ca2⫹ spike-induced LTD
which otherwise failed, and this LTD is sensitive to the
presence of a PKC inhibitor (111). It is notable that a
strong and persistent Ca2⫹ signal produced following the
photolytic release of caged IP3 in peripheral dendrites of
a PC was sufficient to evoke persistent depression in
GA-evoked EPSP (147).
However, it is noteworthy that in cultured or freshly
isolated PCs, IP3 is not required for inducing LTD by
glutamate/depolarization conjunction (408).1) Glutamate
pulses did not cause a significant increase in [Ca2⫹]i. Ca2⫹
transients produced by glutamate/depolarization conjunction and those produced by depolarization alone were not
significantly different. 2) A potent and selective IP3 receptor channel blocker, xestospongin C, did not affect the
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in the cerebral cortex. Phosphodiesterase activity seems
to be regulated trans-synaptically via CFs.
Pharmacological data indicate a role for endogenous
cGMP in LTD induction, because inhibition of phosphodiesterases produces an effect equivalent to intradendritic
injection of cGMP, and either of these induced LTD when
associated with GA stimulation (186, 187). Although immunocytochemical studies failed to reveal the presence
of cGMP in PCs (117, 494), this may have been due to the
strong phosphodiesterase degradation of cGMP.
5. Arachidonic acid and oleic acid
C. Protein Kinases and Protein Phosphatases
Second messengers specifically activate certain protein kinases, which in turn phosphorylate various substrate proteins. The phosphorylating action of protein
kinases is counterbalanced by the dephosphorylating action of protein phosphatases.
1. PKC
Stimulation of a cell by diverse types of first messengers activates the PKC family of serine-threonine protein
kinases, which in turn phosphorylate a variety of substrates. In general, inactivated PKC is present mainly in
the cytosol, whereas its hydrophobic activators are
present on the membrane. PKC activation results in the
translocation of PKC to the membrane, cytoskeletal elements, nuclei, and other subcellular components (384).
More than 10 subspecies of PKC have been identified in
mammalian tissues (413). Four classical PKCs (␣, ␤I, ␤II,
and ␥) are activated by Ca2⫹, phosphatidylserine, and
DAG or phorbol esters; this activation is enhanced and
prolonged by cis-unsaturated fatty acids and lysophosphatidylcholine (489). The other four novel subspecies of
PKC (␦, ⑀, ␩, ␪) are Ca2⫹ independent, and four atypical
subspecies (␨, ␫, ␭, ␮) are Ca2⫹ and DAG independent.
The subspecies PKC-␥ is present in PCs but not in
other types of neurons in the cerebellum, while the ␤I and
␤II subspecies are predominantly expressed in the granular and molecular layers, respectively (28). High-resolution immunogold analysis revealed that PKC-␥ is highly
expressed on the dendrosomatic plasma membrane forming two pools, one associated with the membrane and the
other located within 50 nm of the plasma membrane (78).
PKC-␥ also occurs in dendritic spines of PC, particularly
abundant in and near the postsynaptic density. PKC-␥
appears to have a developmental role, i.e., in the elimination of multiple CF innervations of PCs to attain the
typical single CF innervation onto each mature PC (258).
PKC-␥ mRNA is highly expressed in the dendrite-rich
neuropil of the mouse cerebellum at postnatal day 14,
compared with adult mice, suggesting a role in synaptogenesis (390).
The subspecies PKC-␦ is abundant in PCs located in
the visual- and vestibular-receiving areas in the posterior
lobules (90, 203, 204). In lobules VI–IX, the PKC-␦-containing PCs form distinct parasagittal bands, suggesting a
PKC-␦ role in the specific circuit connection between PCs
and subcortical neurons. The immunoreactivity for PKC-␦
is prominent in the PC somata and is also occasionally
observed in the dendrites, axons, and their terminals
(370). PKC-␦ immunoreactivity is associated with the
rough endoplasmic reticulum, but not detected on the cell
membrane or PC dendritic spines (78). PKC-⑀ is present in
the PC somata and PKC-␨ in the PC somata and dendrites
(554). PKC-␩ and PKC-␪ are present in the PC somata, and
PKC-␭ is also in the PC somata, probably associated with
a 200-kDa neurofilament component, whereas PKC-␫ is
absent in PCs (35).
The PKCs obtained from the cerebellum have also
been classified into types I, II, III, corresponding to the ␥,
␤I/␤II, and ␣ genes, respectively (479). Type I is unique in
its activation by cis-unsaturated fatty acids, to which
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The enzyme PLA2 catalyzes the release of cis-unsaturated free fatty acids such as arachidonic and oleic acids
from membrane phospholipids. Involvement of arachidonic/oleic acids in signal transduction for LTD induction
has been demonstrated by showing that the depressant
effect of manoalide and quinacrine, inhibitors of PLA2, on
LTD is counteracted by coapplication of arachidonic acid
or oleic acid (322).
The free fatty acids act as second messengers on
diverse target molecules. For example, arachidonic acid
is known to stimulate DGK, thereby downregulating the
level of DAG in neuronal membranes, which may in turn
downregulate PKC activity (443). However, arachidonic
acid and its metabolites, or oleic acid, are also known to
strongly stimulate PKC-␥ (479). Arachidonic acid may
activate guanylyl cyclase (524). Even though the relevance of glutamate transporters to LTD induction is unclear, the following reports may be noteworthy. Arachidonic acid enhanced the inward current generated in PCs
by an excitatory amino acid transporter, and PLA2 inhibitors blocked this effect (271). Arachidonic acid decreased glutamate uptake mediated by the type EAAT1
transporter but increased that by the type EAAT2 transporter (576). Arachidonic acid also activated the transporter-mediated proton currents (527).
The roles for diverse metabolites of arachidonic acid,
collectively termed eicosanoids (434, 488), in LTD induction have yet to be investigated. Among them, the prostaglandin D2-binding protein and NAPD-linked 15-hydroxy-prostaglandin D2 dehydrogenase were found to be
localized in PCs of the pig cerebellum (547), but the
presence of these proteins has not been confirmed in
other animal species.
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2. Protein kinase G
Protein kinase G (PKG) is a dimeric cGMP-binding
protein of molecular weight 150,000 consisting of two
identical subunits (mol wt 75,000), each of which contains
two cGMP-binding sites (476). PKG equally catalyzes the
phosphorylation of serine or threonine residues, while
PKA shows a preference for serine. PKG types I and II
have different catalytic and regulatory properties (161).
Type I PKG is highly concentrated in PCs throughout their
somata, dendrites, and axons, whereas type II PKG is
widely distributed in the brain (141). Immunoreactivity
for PKG is observed in all mature PCs of rats after postnatal day 4, but until postnatal day 3, PCs form PKGpositive and -negative clusters, apparently related to the
compartmentalization of the cerebellum (543).
The role of PKG in LTD induction has been demonstrated by showing that a PKG inhibitor, KT5824, effectively blocked the quisqualate-induced presistent reduction of glutamate sensitivity of PCs (236) and GA/CFinduced LTD (186). PKG may contribute to LTD induction
by phosphorylating AMPA receptors as demonstrated
with partial peptides of AMPA receptors (403) (sect.
IVE1). Alternatively, PKG may facilitate LTD induction
through the inhibitory action of PKG-phosphorylated G-
substrate on protein phophatases (sect. IVC7). Some other
possible implication of PKG in LTD induction is noteworthy. 1) PKG activates ADP-ribosyl cyclase to produce
cADPR that acts to release Ca2⫹ from the ryanodinesensitive Ca2⫹ stores (sect. IVB3). 2) PKG may prevent the
thrombin-stimulated production of IP3 and thereby reduce the release of Ca2⫹ from intracellular stores, as
demonstrated in Chinese hamster ovary (CHO) cells
transfected with PKG (457). 3) PKG may mediate the
action of CO to induce a long-lasting change in 3-Na⫹-K⫹ATPase localized in PCs, because this action is absent in
PC-deficient mice, mimicked by 8-bromo-cGMP, and
blocked by inhibition of PKG (409). This action of CO is
probably mediated by mGluRs because it is mimicked by
glutamate and mGluR agonists.
3. Protein tyrosine kinases
Protein tyrosine kinases (PTKs), which transfer the
␥-phosphate of ATP to tyrosine residues, are classified
into receptor-coupled and non-receptor-coupled types.
The receptor-coupled PTKs are associated with neurotrophin and growth factor receptors and regulates cellular
survival, growth, and differentiation, whereas the nonreceptor-coupled PTKs are components of the intracellular signaling cascade (357). PTK activity is high in the
cerebellum, and PCs express neuronal isoforms of c-src
PTK, pp60c-src(⫹) (502), and pp62c-yes, another member
of the src subfamily (578). PCs are also rich in tyrosine
phosphatase, which reverses tyrosine phosphorylations
catalyzed by PTKs (317).
The involvement of PTKs in LTD induction has been
suggested because the two structurally distinct PTK inhibitors, lavendustin and herbimycin A, blocked GA/Ca2⫹
spike-induced LTD (63). Herbimycin A also prevented
depression of GA-EPSPs produced by intracellular infusion of a PKC activator, (⫺)-indolactan V. These results
indicate that PTKs, operating in association with PKC, are
required for LTD induction. PTKs may interact with PKC
directly, but an indirect interaction via the G protein-PLCDAG-PKC pathway is also possible, because PTK inhibitors block Gq/11 protein-coupled receptor-mediated formation of IP3 (528). However, this possibility has to be
considered with caution since inhibitors for tyrosine
phosphatases also blocked the IP3 formation.
A src family nonreceptor PTK, Lyn, has been shown
to be associated with AMPA receptors (193). Lyn PTK is
activated through AMPA receptors independent of Ca2⫹
and Na⫹ influxes, and it in turn activates MAPK in cerebellar primary cultures. Evidence was given to the possibility that activation of MAPK translocates into the
nucleus and regulates expression of brain-derived neurotrophic factor (BDNF) gene, suggesting yet another
pathway in LTD induction (sect. IVD4). A possibility is
also entertained that certain receptor PTKs are involved
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types II and III are almost inert. When attenuation of
voltage-gated K⫹ channels was taken as an index of activation of PKC, perforated patch recording in tissue cultures revealed that PKC in PCs was sensitive to both DAG
and oleic acid, the sensitivity being blocked by a PKC
inhibitor, while PKC in granule cells was insensitive to
oleic acid (331). These results are consistent with the
differential distribution of type I (␥) PKC in PCs and type
II (␤I, ␤II) PKC in granule cells.
Bath application of phorbol esters, activators of PKC,
induced persistent depression of glutamate-induced responses in PCs (105). Phorbol ester-induced LTD in cultured PCs mutually occluded the quisqualate/depolarization-induced LTD (325). Various PKC inhibitors have been
shown to block LTD induction (103, 151, 186, 325). No
LTD occurred in PCs of transgenic mice expressing the
pseudosubstrate PKC inhibitor, PKC-[19O31] (118). However, LTD remains intact in PCs of PKC-␥-deficient mice
(86). It is noted that in PKC-␥-deficient mice, hippocampal
LTP was greatly impaired, while hippocampal LTD remained normal (2). The PKC subspecies involved in LTD
induction in PCs may not be ␥ or, even if it is, it may be
replaced by another subspecies in PKC-␥-deficient PCs.
The PKC involved in LTD induction may not be ␤I, ␤II, ␦,
␭, or ⑀ because of their limited localization (see above).
The possibility may be either ␣, ␩, ␪, or ␨, but in view of
the dependence of the LTD induction on Ca2⫹ (sect. IVA1)
and mGluR-DAG cascade (sects. IIIB3 and IVB1), PKC-␣ is
the most likely candidate.
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CEREBELLAR LONG-TERM DEPRESSION
in LTD induction through their association with IGF-I
receptors (sect. IIIB7).
4. MAPK
5. PKA
Although there is no evidence indicating that PKA is
involved in the induction of LTD (237), it plays a role in
GA-PC transmission on the presynaptic side in connection with GA-LTP. Ca2⫹/calmodulin-sensitive type I adenylyl cyclase, which produces cAMP and thereby activates PKA, is highly expressed in granule cells (91). The
activation of adenylyl cyclase in the GAs appears to be
involved in the induction of LTP in GA-PC synapses by the
tetanus of GAs for two reasons: 1) PKA inhibitors blocked
LTP (324, 461), and 2) forskolin, an activator of PKA,
induced potentiation of GA-PC transmission by increasing
the probability of transmitter release (87). Mice deficient
in type I adenylyl cyclase lacked GA-evoked LTP (499).
6. Ca2⫹/calmodulin-dependent protein kinase
Ca2⫹/calmodulin-dependent protein kinases (CaMKII)
are serine/threonine protein kinases expressed at high
concentrations preferentially in neurons. Of the two isoforms of CaMKII, ␣ and ␤, ␣ is predominant in the fore-
brain (␣/␤ ratio, 3:1), while ␤ is predominant in the cerebellum (␣/␤ ratio, 1:4) (376). In the cerebellum, CaMKII␣
is specifically concentrated in the PC somata and dendrites (537). CaMKII␤ appears to function as an F-actin
targeting molecule for localizing CaMKII␣/␤ heterooligomers to the dendritic spines (480). Arachidonic acid
and its metabolites inhibit CaMKII (435).
Although CaMKII␣ has been implicated in hippocampal LTP induction (446), evidence is scarce for its involvement in cerebellar LTD induction. The CaMK inhibitors
KN-93 and KN-62 potentiated glutamate-induced currents
in cultured PCs (268). Specific roles of CaMKII in PCs
have yet to be identified.
7. Protein phosphatases
Two major types of serine/threonine-specific protein
phosphatases, PP1 and PP2, have been identified. PP1
specifically dephosphorylates the ␤-subunit of phosphorylase kinase and is inhibited by nanomolar concentrations
of proteins, termed inhibitor-1 and inhibitor-2. PP2 dephosphorylates the ␣-subunit of the phosphorylase kinase
preferentially and is unaffected by either inhibitor-1 or
inhibitor-2. PP2 comprises three enzymes: PP2A, PP2B,
and PP2C (95). PP2A, in a manner similar to PP1, does not
require cations for its activity and is sensitive to okadaic
acid, whereas PP2B, called also calcineurin, is Ca2⫹/calmodulin dependent and much less sensitive to okadaic
acid. PP2C is Mg2⫹ dependent and insensitive to okadaic
acid.
The PP1 consists of isoforms having different catalytic units. Strong immunoreactivity for a catalytic unit of
PP1, PP1␥1, but not PP1␦ or PP1␣ was observed in PCs
including the fine dendritic branches and spines (191).
Immunoreactivity for PP2A (␣ and/or ␤) was seen in the
PC somata and thick dendrites, but not in the fine dendrites or spines. mRNAs for PP2A␣ and PP2A␤ are expressed in PCs (1). PP2B is present in the cerebellum
(493). The G substrate specifically contained in PCs becomes a potent inhibitor of PP1 as well as PP2A when
phosphoprylated by PKG (116). The molecular structure
of G substrate has recently been determined (144, 183).
The cloned G substrate inhibits PP2A more sensitively
than PP1 (144).
Bath application of calyculin A or okadaic acid, or
intracellular injection of microcystin LR into PCs, all being potent inhibitors of PP1/2A, induced LTD when combined with GA stimulation (12). Similarly, glutamate-induced currents in cultured PCs were markedly reduced
during repeated application of glutamate pulses in the
presence of calyculin A (268). These effects are presumably due to inhibition of the dephosphorylating action of
protein phosphatases antagonizing phosphorylating action of protein kinases (C and/or G). The observation in
the cerebellum is contrasted to the finding in the hip-
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The MAPK has been implicated in signal transduction
cascades for cell proliferation, cell differentiation, and
early embryonic development, as well as in synaptic plasticity (93). MAPK immunoreactivity is prominently located in cell bodies and dendrites of PCs (148). In cultured PCs, glutamate/K⫹-conjunctive stimulation induced
LTD and at the same time activated MAPK, and both of
these effects were blocked by a specific inhibitor of
MAPK kinase (MAPKK or MEK), PD98059, or an antiactive MAPK antibody (274).
How MAPK is activated in PCs is unknown, but some
possibilities may be pointed out. MAPK could be activated
by Ca2⫹ influx that leads to activation of a small G protein
(Ras), and a Ras-dependent signaling pathway could in
turn activate MEK and MAPK (453). Or, Ca2⫹ influx could
first activate PKC that in turn activates the MAPK cascade. It is also possible that PAF activates MAPK and
MEK, as demonstrated in CHO cells (215). How MAPK
contributes to LTD induction is also unknown, but some
possibilities may be raised. Since PD98059 attenuated the
mGuR1 agonist-induced inward current, it is possible that
MAPK contributes to LTD induction by acting on
mGluR1s (274). Or, MAPK may contribute to LTD induction by activating cPLA2 by phosphorylation (320), or
MAPK and/or its downstream kinases could affect LTD
induction by phosphorylating AMPA receptors. Another
possibility is that MAPK translocates into the nucleus and
regulates the expression of the BDNF gene (193).
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pocampus, in which protein phosphatase inhibitors inhibit LTD induction (394).
D. Other Factors
1. Protein synthesis
strated to occur in neuronal dendrites after stimulation of
mGluRs (549), and a role of a rapidly turned over protein
in the mGluR-mediated or neurotrophin-evoked LTD induction in hippocampal neurons has also been reported
(218, 255). Expression of dendritic mRNA increased following LTP (447). A challenging theme is to identify the
protein that is quickly turned over in synaptic regions of
PCs to play roles in the LTD induction.
2. Gene regulation
A sequential bath application of 8-bromo-cGMP and
AMPA to a cerebellar slice, which induced LTD-like persistent reduction in AMPA sensitivity of PCs (236), resulted in enhanced expression of the immediate early
genes, c-Fos and Jun-B, in PCs (402). Application of
AMPA to the surface of the cerebellum in vivo in conjunction with electric CF stimulation resulted in the expression of Jun-B in PCs (561). GA/CF conjunction in the
cerebellum in vivo also resulted in Jun-B expression,
which was blocked by a NOS inhibitor (563). Jun-B with
c-Fos forms an AP-1 complex, which acts as a transcriptional factor (388), but the mRNAs that are products of
this transcriptional factor remain to be identified.
The cAMP response element-binding protein (CREB)
is a nuclear protein regulating the transcription of genes
with a CRE site in their promotor. When synaptic activation causes a high [Ca2⫹]i, CREB is phosphorylated at its
transcriptional regulatory residue, serine-133, by involving CaMKIV. When transfected with a dominant inhibitory
form of CREB that prevents DNA binding of endogenous
CREB, or with dominant-negative constructs of CaMKIV,
PCs failed to develop the late phase of LTD, just as they
did under the influences of transcriptional inhibitors (5).
CREB and CaMKIV are, therefore, suggested to contribute
to the late phase of LTD. Genes encoding ␣ and ␤ polypetides of CaMKIV are highly expressed in cerebellar
granule cells, but their expression in PCs is unclear (458).
CaMKIV/Gr-deficient mice exhibited impaired neuronal CREB phosphorylation and Ca2⫹/CREB-dependent
gene expression, and cultured PCs derived from these
mice lacked the late phase of LTD (211). CaMIV null mice
exhibited significant reduction of mature PCs in number
and the expression of carbindin 28K in individual PCs
(446). These effects make it difficult to simply ascribe the
observed locomotor defect to the possible lack of the late
phase of LTD.
3. Glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is an intermediate filament protein specifically expressed in astrocytes.
In the cerebellum, it is highly expressed in the Bergman
glial cells, a subset of astrocytes. GFAP-deficient mice
exhibited normal cerebellar architecture and synaptic
transmission but failed to produce GA/CF-induced LTD
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Not only somata but also dendrites contain a number
of different mRNAs and the translational machinery including ribosomes, polyribosomes, and elongation factor
2, as well as the endoplasmic reticulum and cisternae of
the Golgi apparatus. Protein synthesis appears to occur in
both somata and dendrites of neurons in association with
synaptogenesis and synaptic plasticity.
The requirement of protein synthesis for the induction of LTD has been demonstrated by using translational
inhibitors (anisomycin, puromycin, and cycloheximide).
mRNA cap analog has also been used for preventing
translation (218, 267). The translational inhibitors depress
the late phase of LTP in hippocampal neurons (152, 153,
411). In cultured PCs, translational inhibitors continuously applied immediately after conjunctive stimulation
depressed LTD only after 45 min (323). A current view is,
therefore, that protein synthesis serves specifically for
long-term maintenance of synaptic plasticity.
However, another role of protein synthesis has recently been proposed because translational inhibitors
abolish the entire LTD including its early phase in PCs of
cerebellar slices (267). In cerebellar slices, a 5-min pulse
application of a translational inhibitor depressed protein
synthesis, determined by methionine incorporation, to
one-half or less quickly and persistently over 30 min.
When applied around the time of conjunctive stimulation,
a 5-min pulse application of translational inhibitors
blocked LTD induction quickly and persistently, indicating that LTD induction requires a quickly turned over
protein(s). Because a translational inhibitor pulse no
longer affects LTD induction when applied with a delay of
15 min or more after the onset of conjunctive stimulation,
the protein appears to play its role in the LTD induction
only in a narrow time window within 15 min from the
onset of conjunctive stimulation. A 5-min pulse application of a transcriptional inhibitor (actinomycin D or DRB)
also effectively blocked LTD induction when it proceeded
conjunctive stimulation 30 min or more (267).
Another recent finding that 5-min pulse applications
of translational inhibitors depress mGluR-EPSPs quickly
and persistently (266) provides a means to follow changes
in the concentration of rapidly turned over protein(s) in
PCs. Because the peak amplitudes of mGluR-EPSPs were
progressively depressed over 30 min after a 5-min pulse
application of a transcriptional inhibitor, transcription
appeared to be persistently inhibited so that mRNAs were
gradually depleted during the 30-min delay time (266).
Rapid turning over of a protein has been demon-
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CEREBELLAR LONG-TERM DEPRESSION
(482). What is missing in GFAP-deficient mice in terms of
signal transduction for LTD induction has not yet been
clarified. However, because the membranes of the Bergman glial cells possess AMPA receptors and glutamate
transporters, it may well be thought that the Bergman
glial cells, responding to GA and/or CF activation, secrete
a yet unknown diffusible factor that may be required for
LTD induction.
4. BDNF and tissue plasminogen activator
E. Inactivation of AMPA Receptor
The complex signal transduction initiated by CF/GAconjunctive stimulation or equivalent reduced form of
stimulation eventually results in the inactivation of AMPA
receptors mediating GA-CF transmission. Various possible mechanisms of the inactivation have so far been examined.
1. Phosphorylation
Protein phosphorylation has been shown to be a
major mechanism for regulating ligand-gated ion channels
such as nicotinic acetylcholine receptor, GABAA receptor,
as well as ionotropic glutamate receptors. AMPA receptors have a large extracellular NH2-terminal domain, one
membrane hairpin loop, three transmembrane domains, a
large extracellular loop between transmembrane domains
TM3 and TM4, and an intracellular COOH-terminal domain. AMPA receptors can be phosphorylated at their
serine, threonine, or tyrosine residues. Several phosphorylation sites have been located in GluR1– 4 and -6 subunits. In the COOH-terminal domain of GluR1, serine-845
and serine-831 are phosphorylated by PKA and PKC, respectively (449). The serine-831 of GluR1 is also phos-
phorylated by CaMKII (38, 355). As related specifically to
LTD, the serine-880 residue of GluR2 subunit is phosphorylated by PKC (92, 365).
A synaptic cytoskeletal protein includes a PDZ domain (named after three proteins containing the motif,
PSD-95, Dig-A and ZO-1) containing modular protein-protein interaction motifs that specifically bind the COOH
termini of membrane-associated proteins. Glutamate receptor-interacting protein (GRIP), AMPA receptor binding protein, and protein interacting with C kinase 1 (PIK1)
are synaptic PDZ domain-containing proteins, which anchors the COOH terminus of GluR2/GluR3 subunits of
AMPA receptors (126). It has recently been demonstrated
that phosphorylation by PKC drastically reduces the affinity for GRIP at serine-880 of the GluR2 COOH terminus
(38, 365, 559). Peptides, reproducing the phosphorylated
and dephosphorylated GluR2 COOH-terminal PDZ binding motif, attenuated the glutamate/depolarization-induced LTD in cultured PCs (559). These findings suggest
that unbinding of AMPA receptors from cytoskeletal proteins primes AMPA receptors for further steps of LTD
induction (see below).
Attention has been paid also to serine-696 of GluR2
subunit, because a partial peptide that contained phosphorylated serine-696 (12P3) labeled the PC dendrites
persistently following inactivation of AMPA receptors by
combined chemical stimuli (8-bromo-cGMP plus AMPA,
phorbol ester plus AMPA, calyculin A plus AMPA, or
quisqualate alone) in cerebellar slices (403, 404). The
immunoreactivity was localized at the dendritic spines
synapsing with GAs and was inhibited by a Ca2⫹ chelator
(BAPTA-AM), a PKC inhibitor (calphostin C), or an
mGluR antagonist (MCPG). However, because the serine696 site is located in the extracellular loop between TM3
and TM4 domains (319, 503), it is unclear how it can be
phosphorylated by PKC and PKG located intracellularly
or in the membrane, unless the membrane topology of the
GluR2 subunit is different in PCs or an activity-dependent
translocation occurs dynamically between TM3 and TM4
domains. Or, alternatively, phosphorylation at serine-696
may occur before the intradendritically transported
GluR2 subunits are incorporated into the subsynaptic
membrane.
2. Desensitization and modulation
Desensitization is a phenomenon in which a receptor
is inactivated during prolonged activation by agonist molecules, and its rate is regulated by phosphorylation. In
outside-out patches obtained from rat PCs, GluR desensitization developed fast with a similar time constant in
patches from dendrites (5.37 ms) and somata (5.29 ms)
(192). The possibility that LTD is due to a persistent
desensitization occurring in phosphorylated AMPA receptors is supported by an observation using aniracetam,
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While BDNF has been implicated in LTP induction in
the hippocampus (255), evidence is scarce regarding its
involvement in cerebellar LTD induction. Nevertheless,
when quisqualate application induced LTD, a significant
increase in BDNF mRNA expression occurred in cerebellar tissues with a peak 4 h after the application, suggesting
that BDNF plays a role in the later phases of LTD (574).
Even though the major source of the BDNF mRNA increase was located in the granule cell fraction, the PC
fraction also contained BDNF mRNA, which was increased by quisqualate application. The BDNF genes appear to be regulated by MAPK (sect. IVC4).
Tissue plasminogen activator (tPA) has been implicated in development and regeneration of neurons. Expression of mRNAs for tPA have been reported to increase in PCs within 1 h after rats were trained for a
complex motor task (478). However, no evidence is yet
reported to indicate a role of tPA in LTD induction.
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3. Internalization of AMPA receptors
Internalization by endocytosis provides a mechanism
of removing receptors from synaptic membranes (64, 213,
348). Internalization of AMPA receptors by endocytosis
was induced by activating cultured hippocampal neurons
with AMPA and visualized by labeling with an antibody
against GluR1 (80). Furthermore, the decrease in the number of clustered AMPA receptors was observed at synapses on cultured hippocampal neurons, concurrent with
induction of LTD (79). Quisqualate/depolarization-induced LTD in cultured PCs was blocked by peptides of
dynamin and amphiphysin, which interfere with the clathrin endocytotic complex and which also blocked IGF-Iinduced attenuation of AMPA receptor-mediated currents
(542). The LTD-induction protocol of phorbol ester plus
AMPA application resulted in internalization of AMPA
receptors in cultured PCs (364). These observations suggest that endocytotic internalization of the AMPA receptors unbound from the GRIP/ABP is the final step of LTD
expression in PCs is. PICK1, however, also appears to
play a role in internalization (559).
F. Chemical Network for LTD
The diverse signal transduction processes implicated
in LTD induction in PCs are summarized in Figure 5. They
can be roughly classified into the following seven major
pathways: 1) GA glutamate3 AMPA receptor3 Na⫹/Ca2⫹
influx; 2) GA glutamate3mGluR1a3 Gq/11 protein3 PLC
relayed by DAG3 PKC (2⬘) and IP33 IP3 receptor3 Ca2⫹
release (2⬘⬘); 3) GA glutamate3mGluR1a3 G protein3
PLA23arachidonic/oleic acids; 4) GA NO3guanylyl cyclase3cGMP/PKG probably relayed by G substrate3
protein phosphatase; 5) CF amino acid transmitter3glutamate receptors3 Na⫹/Ca2⫹ influx; 6) CF CRF3 G
protein3 PKC; 7) CF IGF-I3internalization. GFAP and
BDNF may provide other inputs to PCs, and PTKs, MAPK,
immediate early genes, and a yet-unidentified rapidly
turned over protein(s) also participate in LTD induction.
There are a number of interconnections between the different pathways. For example, interaction is expected to
occur from 2⬘ and 3 to 4 since guanylyl cyclase can be
activated by PKC as well as by arachidonic acid (524). A
loop connection has been suggested to subserve selfregeneration, which rapidly builds up the initial phase of
synaptic plasticity before it is stabilized in a certain structural change (51, 333). However, there is yet no clear
evidence for such a self-regeneration in LTD induction
(see sect. IVB5).
GA/CF- or GA/Ca2⫹-spike-induced LTD in cerebellar
slices involve all of these pathways, and interference with
any of them results in the blockade of LTD induction.
However, reduced forms of LTD do not necessarily require all of them. For example, glutamate/depolarizationconjunction induces LTD in cultured PCs without involving 2⬘⬘, 4, or 6. LTD can be induced even by a single
procedure, which, however, triggers complex signal transduction processes. K⫹-induced depolarization causes LTD
(101), but in this case, transmitters are released from
depolarized presynaptic terminals and Ca2⫹ and Na⫹ enter depolarized PCs. Quisqualate alone also induces LTD
(236, 574), but it activates both AMPA receptors and
mGluRs, and again allows the entry of Ca2⫹ and Na⫹ into
PCs during membrane depolarization. Photolysis of caged
IP3 alone within a PC dendrite also induce LTD (147). In
this case, though, it is expected that a large increase in
[Ca2⫹]i in turn activates a number of Ca2⫹-dependent
enzymes such as PKC and PLA2, which would catalyze
reactions identical to those resulting from activation of
mGluRs. The final event in the signal transduction for LTD
appears to be phosphorylation of AMPA receptors in GAPC synapses, which would in turn result in reduced efficacy of the AMPA receptors due to their desensitization
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which is known to markedly reduce desensitization of
AMPA receptors. Aniracetam prolonged the decay of the
GA-evoked EPSC (time constant of decay from 11.74 to
15.98 ms) and compensated for the reduction in EPSCs
during GA/Ca2⫹-induced LTD (197). However, the decay
time course of GA-evoked EPSC in normal perfusates was
not modified during LTD. This seeming contradiction may
be reconciled by assuming that the fraction of AMPA
receptors desensitized during LTD does not contribute to
the EPSC, while the other AMPA receptors maintain normal kinetics and desensitization properties.
Another challenge to the desensitization hypothesis
is the observation that the activation of AMPA receptors
is not always required for LTD induction. LTD can be
induced by combined activation of mGluRs with a Ca2⫹
spike in the presence of CNQX (198) or by photolysis of
caged IP3 in the PC dendrites (147). A reconciling explanation may be that desensitization is an initial step that
can be skipped if further changes in AMPA receptors such
as declustering or internalization (see next section) are
directly triggered by application of sufficiently strong
stimuli.
In addition to desensitization, it is possible that the
properties of AMPA receptors are modulated by the action of PLA2 on the phospholipid moiety of the membrane-containing AMPA receptors (52). In synaptoneurosomes obtained from rat hippocampus, PLA2 affected the
[3H]AMPA binding to the AMPA receptor bimodally; at
low concentrations, PLA2 inhibited binding and at high
concentrations enhanced it (84). A PLA2 inhibitor prevented the depolarization-induced increase in [3H]AMPA
binding to AMPA receptors (47), and an activator of PLA2
increased the AMPA receptor affinity (46) in rat brain
synaptoneurosomes.
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V. MODELS FOR FUNCTIONAL ROLES OF
LONG-TERM DEPRESSION
As reviewed in sections III and IV, research in recent
years has been fruitful in elucidating cellular and molecular mechanisms of LTD. However, different approaches
are required for identifying roles of LTD in cerebellar
functions. These are 1) behavioral studies of animals in
which LTD is manipulated, either pharmacologically or
genetically; 2) recording of signals from cerebellar neurons correlated to behavior by not only electrophysiological but also by optical recording and brain imaging techniques; 3) computational modeling of the cerebellum as a
network and a system incorporating LTD as an essential
component and examination of its operation by computer
simulation. In the initial stages of research, we usually
move in the order from the experimental (1 and 2) to
theoretical (3), but at an advanced state of research, the
order may be reversed. Section V thus focuses on the
microcomplex model of the cerebellum, and section VI
examines it in the light of the evidence accumulated in
recent experimental studies of various forms of motor
learning.
A. Corticonuclear Microcomplex
1. Structure
The corticonuclear microcomplex (hereafter referred to as a microcomplex) has been proposed as the
functional module of the cerebellum, which has a skeleton structure such that a cortical microzone is paired with
a small distinct group of neurons in a cerebellar or vestibular nucleus (227). The MF afferents arising from various precerebellar nuclei supply excitatory synapses to
granule cells in the microzone and also to the nuclear
neurons via collaterals. Another set of afferents to the
microcomplex is relayed by a small distinct group of
inferior olive neurons, whose axons end as CFs on PCs
and also supply excitatory synapses to the nuclear neurons via collaterals (Fig. 6). Figure 6 further illustrates
three accessory circuits attached to a microcomplex,
FIG. 6. Neuronal circuit structure in the cerebellum.
CC, cerebellar cortex; NN, cerebellar and vestibular nuclei; IO, inferior olive; PN, precerebellar nucleus; RN, red
nucleus (parvocellular part); MF, mossy fiber; CF, climbing fiber; PC, Purkinje cell; GR, granule cell; PF, parallel
fiber; BC, basket cell; SC, stellate cell; GO, Golgi cell; open
triangle, excitatory synapse; solid triangle, inhibitory synapse. [From Ito (232). Copyright 2000 Elsevier Science.]
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and/or modulation and eventually in their removal from
postsynaptic membrane by internalization. Any stimulus
will induce LTD if it leads to sufficient phosphorylation
and/or modulation of the AMPA receptors. To this end,
Ca2⫹, indispensable for activating a number of enzymes
including PKC and PLA2, is the key factor for LTD induction.
Some important properties may emerge from the
elaborate chemical networks of signal transduction described in sections III and IV. For example, integration of
signals across multiple time scales, generation of distinct
outputs depending on input strength and duration, and
self-sustained regeneration (51). Such integration of signals across multiple time scale could provide an explanation how CF signals delayed after GA signals still induce
LTD (sect. IIA3), as proposed theoretically (216, 472, 495).
Nonlinear accumulation of signals may occur in the network, which would also explain the frequency dependence and requirement for certain numbers of repetition
in LTD-inducing stimulation (sect. IIA4). These emergent
properties may provide a safety device that prevents an
incidental occurrence of LTD when it is unnecessary and
which enables LTD to occur robustly whenever the conditions for its occurrence are satisfied. A possibility is also
raised that an adaptive increase of the learning rate occurs due to much longer time constants of the chemical
events underlying LTD than electrical signals; this “learning” of the learning rate would robustly improve the learning capability of the cerebellum (471).
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namely, nucleocortical and nucleoolivary projections and
dentatorubroolivary triangle (see sect. VD).
A typical microcomplex structure is found in the
flocculus associated with the VOR system (Fig. 7). Several
microzones have been identified in the flocculus by microstimulation, which evoked either horizontal, vertical,
or rotatory eye movement presumably through their connections to a component of VOR subserving eye movements in these directions (399, 464, 531). These microzones receive CF inputs related to respective VOR
components (176, 240). Another microcomplex has been
dissected from the C3 zone of the cerebellum (249). It is
connected to motoneurons innervating a finger via the
anterior interpositus and red nucleus and receives CF
signals from the surface of the same finger via the cutaneous afferents, dorsal column nucleus, and inferior olive.
The microzones defined in the paravermis (422) and
in the flocculus (Fig. 7) may have a size of ⬃10 mm2. In
rats, one microzone of this size contains ⬃10,000 PCs and
274 times more granule cells (190). The human cerebellum is ⬃50,000 mm2 wide so that it may contain as many
as 5,000 microzones as its functional unit (227).
2. Operation
Four basic notions consitute the operational principle of a microcomplex (Fig. 6). 1) MF signals passing to a
microzone are relayed by granule cells and in turn excite
PCs and other cortical neurons, eventually evoking simple
spikes in PCs. Thus, in each microcomplex, simple spike
discharges of PCs driven by MF signals would produce a
unique functional state due to concerted activities of excitatory and inhibitory synapses on PCs, such as visualized in a computer simulation study (114). 2) The MF
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FIG. 7. Microzone in the flocculus related to the vestibuloocular reflex (VOR). A: side view of the left flocculus
of rabbit. Microzones are mapped by local electrical stimulation through a microelectrode. Horizontal (H), vertical
(V), rotatory (R) eye movements or eyeblink (E) was
evoked from the shaded areas. [From Nagao et al. (399).
Copyright 1985 Elsevier Science.] B: neuronal circuit for
the horizontal VOR. Arrows filled in black, excitatory connections; those shaded, inhibitory connections; LB, labyrinth. HC, horizontal canal; FL, flocculus; LR and MR,
lateral and medial rectus muscles; AB, abducens motoneuron; OM, oculomotor neuron; PT, pretectal neuron. [From
Ito (230). Copyright 1998 Elsevier Science.]
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CEREBELLAR LONG-TERM DEPRESSION
B. Roles of GAs
1. Ascending segment of GA
The structure of a microcomplex is complicated by
the presence of two types of GA-PC synapses, one formed
with the ascending segments of GAs and the other formed
with PFs (sect. IIA1). A recent study shows that PC dendritic spines contacting the ascending segments of granule cell axons are located exclusively on the smallest
diameter, distal regions of the PC dendrites, while PF
synapses are on the intermediate and large diameter regions of the spiny branchlets (181). The ascending segments form ⬃20% of the GA-PC synapses.
Two modes of activation of PCs by GAs have been
reported as corresponding to these two segments. When
PFs on the surface of the cerebellum are stimulated, a
narrow beam of PFs conduct impulses over a distance of
1 mm, which excite PCs, as visualized using voltagesensitive dyes (94, 536). However, stimulation of MFs in
the white matter of an isolated perfused guinea pig cerebellum induced a circular, nonpropagating patch of synchronized activity, and this is interpreted as representing
activation via the ascending segments of GAs (94). Electrophysiological recording in anesthetized cats, however,
revealed the propagation of PF signals exciting PCs to
over 1.5 mm outside of the granule layer zone activated by
a small set of MFs (164). An intriguing question is why
impulses initiated from the granule cells did not propa-
gate to PFs via the ascending axons in Cohen and Yarom’s
(94) experiment.
Since there are significantly more synaptic vesicles
contained in ascending segments than in PFs (181), the
ascending segment synapses may have a higher transmission efficacy than PF-PC synapses. The ascending GA-PC
synapses are located in the distal PC dendrites, where CF
terminals do not reach (424) and CF-induced Ca2⫹ spikes
do not reliably spread (378). For these two reaons, it may
appear that these synapses produce the homosynaptic
LTD, which does not require CF signals and which plays
other roles than error-driven LTD-based learning (sect.
IIA2). The PF-PC synapses located in the intermediate or
larger diameter regions of the spiny branchlet could be
the site of GA/CF-induced LTD. So far, the two types of
synapses have been mixed in experiments on LTD, and it
is desirable to examine them separately to define their
respective functions in a microcomplex.
2. Length of PFs
Another complication of the microcomplex structure
concerns with the length of PFs that exceeds the width of
a microzone. In contrast to the width of microzones as
narrow as 0.3 to 1 mm [cat (249, 422), rabbit (399)], the
length of PF branches from their bifurcation to their
terminal has been estimated to be as long as 2–3 mm
[chicken and monkey (393), rat (190, 432)].
Physiological data, however, indicate that excitation
of PCs via PFs does not spread more than a distance of
⬃1.5 mm from the site of stimulation (164, 536). In Heck’s
(196) experiment on the rat and guinea pig cerebellum in
vitro, 11 electrodes were linearly aligned at 130-␮m intervals and placed in the granular layer. Stimuli travelling
from electrode to electrode at a velocity comparable with
the conduction velocity of PFs elicited population spikes
of PFs, which linearly increased with the distance and
were saturated for distances longer than 1.0 mm. This
again suggests that the PF spikes are conducted for a
distance of 1 mm but no more. These data may suggest
that the very peripheral segments of PFs do not generate
conducting action potentials, but there could still be electrotonic spread of membrane depolarization for a certain
distance, which could cause release of transmitter.
A concern from a computational point of view is that
PF beams distribute information conveyed by MFs to
more than one microzone. Information of MFs may
spread in the cerebellar cortex via branches of MF terminals and further via PFs across boundaries of microzones.
However, how a microcomplex acquires its functional
specificity out of such broad input connections can be
speculated in the following way along with the microcomplex concept (Fig. 8). Suppose that when signals in a set
of MFs activate PCs in a number of microcomplexes
through the divergent MF-GA-PC connections, PC inhibi-
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signals also drive the nuclear neurons, which generate
output signals of the microcomplex under inhibitory influences of PCs. 3) CFs convey error signals to a microcomplex regarding the operation of the neural system that
includes the microcomplex. The error signals are generated by various neuronal mechanisms in diverse preolivary structures. 4) CF error signals induce LTD in the
conjointly activated GA-PC synapses (learning rule) and
thereby modify the operation of the microcomplex until
the error signals are minimized. CF signals evoke complex spikes in PCs, and hence induce conducting impulses
in PC axons, which eventually evoke IPSPs in the nuclear
neurons. However, CFs normally fire irregularly at a slow
rate around 1 Hz, compared with the high firing rate of
simple spikes around 50 Hz. Furthermore, the effects of
the IPSPs in nuclear neurons are counteracted by the
EPSPs evoked via collaterals of olivocerebellar fibers.
Therefore, the author suggests that the major role of CF
signals in PCs is to induce LTD, but not to influence the
nuclear neurons via impulse traffic (227).
The above-postulated operation of the microcomplex
has been reproduced by computer simulation using elaborate neuronal network models of the microcomplex including inhibitory neurons in the cerebellar cortex (156,
471, 473).
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Volume 81
the microcomplex in the given motor control. Microcomplexes initially kept inhibited through the preexisting divergent MF-GA-PC connections will thus individually acquire a specific functional involvement through CF errordriven LTD-based learning.
C. Other Types of Synaptic Plasticity
A third complication in the microcomplex structure
is the presence of several other types of synaptic plasticity than conjunctive LTD.
1. Homosynaptic LTD in GA-PC synapses
FIG. 8. Multiple microzone structure of the cerebellum. a–e, Five
neighboring microzones are assumed to be associated with a functional
system. All of these microzones are originally activated by a common
MF-PF pathway, and PC inhibition dominates in nuclear neurons (NN).
Drives through the MF-PF pathway, therefore, will not yield output
signals of nuclear neurons. When errors involved in the repeated operation of a functional system are fed to microzone b, LTD releases its
nuclear neurons from PC inhibition. Microzone b would then operate
with the functional system. Despite divergence of the MF-PF pathway to
multiple microzones, specificity of each microzone will be secured in
this way by the information conveyed by CFs.
tion dominates in them. However, if one of these microcomplexes is involved in execution of a motor control, the
consequently arising CF error signals will induce LTD in
this microcomplex (b in Fig. 8). In the cerebellar cortex of
this microcomplex, the excitatory action of GA-PC synapses will then be reduced, but the excitatory action of
GAs on basket and stellate cells remains and may surplus
GA-PC excitation so that PCs will be inhibited. Thus
nuclear neurons are released from PC inhibition and add
to the output of the microcomplex responding to the MF
input. This process could continue until an adequate number of nuclear neurons are released from PC inhibition to
generate an activity required for the optimal operation of
2. Heterosynaptic LTD in GA-PC synapses
Recent observations that LTD spreads to neighboring
synapses up to 100 ␮m from those involved in GA/CF
conjunction (189, 445, 539) make the input specificty for
LTD ambiguous. Wang et al. (539) guess that conjunction
involving one PF causes LTD in 600 PFs. However, Reynolds and Hartell (445) recognized that LTD did not spread
to the neighboring synapses when these were left unstimulated at all for 20 min. LTD developed only after
their stimulation at 0.2 Hz was resumed for monitoring
LTD. Therefore, heterosynaptic LTD occurs only in those
neighboring synapses that are active even at a low rate of
0.2 Hz during the postconjunction period for 20 min. In
other words, LTD is induced not only in those synapses
directly coactivated with CF signals, but also in the neighboring synapses activated in a loose time relationship
with CF signals. If this is the case, the input specificity of
LTD still holds in a wider sense.
Heterosynaptic LTD may reduce the memory capacity of a Perceptron-like neuronal network, but spreading
memory may bring a certain advantage such as has been
discussed for spread of LTP in hippocampus neurons.
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The homosynaptic LTD occurring after relatively
strong stimulation of GAs alone (188) could represent a
normalizing process against overstimulation of GA-PC
synapses (113). Alternatively, it could be involved in a
type of learning in which there is no specialized input
lines for error signals. Any MF input that evokes GA
signals sufficiently strong to cause Ca2⫹ entry to a PC
could serve as error signals and depress other GA inputs
conjunctively imposed to the PC. This type of learning
without a specialized error signal system occurs in the
part of a fish cerebellum devoid of CFs (44, 45). In the
cerebellar cortex equipped with CFs, both types of learning appear to be implemented in superposition. However,
as pointed out in section VB1, homosynaptic LTD could be
a major learning mechanism in the peripheral branchlets
of PCs, where CF terminals do not reach (424) and CFinduced Ca2⫹ spikes do not reliably spread (378).
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3. Presynaptic LTP in GA-PC synapses
Brief stimulation of GAs at 2– 8 Hz induces LTP in
PCs (104, 207, 459), which is due to an increase in the
release of transmitters from GA terminals (see sect. IVC5).
The observation that LTD is induced postsynaptically and
LTP presynaptically in PCs is in contrast to that in pyramidal cells, where tetanus-induced LTD is converted to
LTP depending on the postsynaptic membrane potential
which determines [Ca2⫹]i (25, 566). A seeming conversion
from LTD to LTP was reported to occur in PCs during
intracellular injection of a Ca2⫹ chelator (485), but the
possibility is not excluded that presynaptic LTP was simply unmasked by the disappearance of LTD. In cultured
hippocampal neurons, repetitive postsynaptic spiking
within a time window of 20 ms after presynaptic activation has been reported to result in LTP, whereas postsynaptic spiking within a window of 20 ms before the repetitive presynaptic activation led to LTD (52). However, no
such conversion between postsynaptic LTD and presynaptic LTP has been observed in PCs by changing the
timing of CF and GA stimulation.
4. Homosynaptic LTD in CF-PC synapses
Homosynaptic LTD occurs also in CF-PC transmission during stimulation of CFs at 5 Hz for 30 s (184).
Signal transduction for this CF-LTD overlaps that for
GA/CF conjunction-induced LTD. The functional meaning
of the modest depression (by 20 –30%) of large all-or-none
CF-evoked EPSCs is unclear for the present, but since
such depression of CF responses does not occur during
CF stimulation at 1 Hz (265), it may imply a possibility
that the effects of CFs to induce conjunctive LTD or
rebound facilitation (see below) decline after excessive
activation of CFs.
5. Rebound potentiation of inhibitory synapses on PCs
CF activation in PCs is followed by a prolonged
potentiation of GABAA receptor-mediated IPSPs (rebound potentiation), which is due to a Ca2⫹-dependent
upregulation of postsynaptic GABAA receptor function
(262) and involves activation of CaMKII (261). Correspondingly, photolytic release of IP3 in PCs combined
with membrane depolarization resulted in facilitation of
inhibitory postsynaptic currents, while it induced LTD in
GA-evoked EPSCs (280). Rebound facilitation may have a
synergistic action with LTD in releasing a microcomplex
from PC inhibition (Fig. 8).
6. LTP in MF-GA synapses
LTP is induced at MF-GA synapses after a high-frequency stimulation of MFs paired with membrane depolarization. This LTP induction involves NMDA receptors,
mGluRs, Ca2⫹, and PKC (107) and is accompanied by
changes of intrinsic excitability of granule cells (24). In
the three-layered Simple Perceptron model of the cerebellum, connections of MFs to granules cells at the second layer perform certain transformation of MF inputs
and provide the decision hyperspace where PCs select
connections for their correct responses (15). In this
model, if MF-GA LTP increases functionally the divergence number from a mossy fiber to granule cells, it is
expected that the dimension of the hyperspace expands
so that the computational capacity of the model is enhanced.
7. Excitability of nuclear neurons
The presence of synaptic plasticity at the major excitatory input to nuclear neurons has been suggested
(332). There is a report of such LTP in vivo (440), but a
recent observation in rat cerebellar slices revealed no
presynaptic tetanus-induced increase of EPSPs in cerebellar nuclear neurons except for some broadening of the
EPSP duration (9). Instead, Aizenman and Linden (9)
found in nuclear neurons a marked increase of the membrane excitability as represented by an increase of the
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LTP induced in a neuron by pairing 1-Hz presynaptic
stimulation and membrane depolarization was shown to
spread to neighboring neurons, which displayed LTP in
those synapses activated by the 1-Hz presynaptic stimulation under no membrane depolarization (470). These
synapses in neighboring cells were not imposed with
membrane depolarization, and therefore they should not
have displayed LTP unless an intercellular influence
reached them from the cell undergoing LTP. Diffusible
substances such as NO, CO, and arachidonic acid may be
considered as its mediator. In the hippocampus, a small
number of synapses involved in generation of LTP influence many other synapses in the vicinity, which have
recently been active. Here, learning is thought to occur
not at levels of individual synapses, but rather at levels of
small local volumes (volume learning, see Ref. 386).
Exact meaning of heterosynaptic LTD in the operation of cerebellar network needs to be explored further.
One likely situation to be considered is that, in natural
conditions, MF signals from a source may reach synapses
in a segment of a PC dendrite after being temporally
dispersed across successive relays. Conjunctive activation with a time-limited occurrence of CF error signals
during behavior may take place only with some of these
synapses. Nevertheless, LTD could spread to all other
synapses located nearby and receiving the dispersed MF
signals. This model assumes local volumes in the cerebellar cortex as mapping MF inputs. To test the validity of
this model, one needs to investigate how MF signals
arising from a source are represented in PC dendrites.
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number of spikes evoked by a given depolarizing pulse.
The membrane excitability change depends on a Ca2⫹
load imposed by activation of NMDA receptors or direct
current injection. In in vitro whole brains of guinea pig,
excitatory input from the vestibular nerve to vestibular
nuclear neurons was paired with the inhibitory input from
flocculus PCs and revealed no traces of synaptic plasticity
in the vestibular nucleus neurons, whereas paired stimulation of the vestibular nerve and inferior olive effectively
induced LTD in flocculus PCs (31). Hence, there is no
evidence for input-specific synaptic plasticity in the major
excitatory synaptic input to the nuclear neurons.
Tetanic stimulation of inhibitory synapses on cerebellar nuclear neurons, presumably supplied by PC axons,
results in long-lasting depression (389). This depression is
due to a reduced postsynaptic GABA sensitivity caused by
increases in [Ca2⫹]i and activation of protein phosphatases in nuclear neurons but does not require activation of
the GABAA receptors. This synaptic plasticity explains
how the increased discharge in PCs in the absence of CF
activity (96) results in a decreased efficacy of PC inhibition of nuclear neurons (54, 239, 264). Tetanic induction
of IPSPs in nuclear neurons also induced a prominent
rebound excitation and associated Na⫹ spike burst upon
release from hyperpolarization, which are regulated by
[Ca2⫹]i (8). A long-lasting increase or decrease of the
IPSPs, depending on the amount of rebound-induced
spikes, followed the rebound excitation (10). The effects
described above in sections VC7 and VC8 may add to
use-dependent flexibility of the microcomplex structure.
However, because these effects are input nonspecific, it is
uncertain how far they afford the simple divergence-convergence connections in a cerebellar nucleus of a capacity to maintain elaborate memory information.
D. Accessory Circuits
1. Nucleocortical projection
Collaterals of axons that larger nuclear neurons send
to the red nucleus, thalamus, and other brain stem structures pass back to the cerebellar cortex (368, 520, 521).
These fibers terminate in the cerebellar cortex as mossy
fibers. The nucleocortical projection is mainly reciprocally organized with corticonuclear projections by PCs
(71, 123, 124, 522). Because the nuclear neurons supply
excitatory synapses to brain stem structures, and because
the major transmitter of the nucleocortical projection is
glutamate, but not GABA (41, 296), the nucleocortical
projection should have excitatory action upon granule
cells as mossy fibers. Because the nucleocortical projection would activate PCs that in turn inhibit nuclear neu-
rons, it may stably maintain the activity of nuclear neurons at a low level in the manner of negative feedback. If
LTD occurs in the GA-PC synapses activated by the nucleocortical feedback, the negative feedback will be removed so that nuclear neurons may maintain a higher
activity. If this is the case, the nucleocortical projection
will add to the release mechanism of an error-driven
microcomplex from dominating PC inhibition as postulated in Figure 8.
2. Nucleoolivary projection
Smaller GABA-containing neurons that occupy 31.7%
of nuclear neurons (41) are the source of the nucleoolivary inhibitory projection (119). The function of this nucleoolivary projection has been suggested to regulate the
occurrence of LTD in PCs by providing negative feedback
information to the olive. For example, when a learned
response reaches a sufficient amplitude, the olive would
be inhibited and further learning blocked (201, 281, 475).
This suggestion has been supported in studies on classic
conditioning (see sect. VIA2). The nucleoolivary projection may thus have an action of protecting a microcmplex,
which has already learned, from further modification. A
modeling study suggests that inclusion of the nucleoolivary inhibition into cerebellar cicuitry makes learning
stable (495).
3. Dentatorubroolivary triangle
Cerebellar nuclei send excitatory synapses to neurons in the parvocellular part of the red nucleus, which
also receive excitatory input from the parietal association cortex (417). Parvocellular red nucleus neurons in
turn send axons to the inferior olive (72, 73). The
rubroolivary projection supplies GABA-negative, excitatory synaptic terminals to inferior olive neurons (119,
120). Because inferior olive neurons supply excitatory
synapses to cerebellar nuclear neurons via collaterals
of CF afferents, the dentatorubroolivary triangle may
form a reverberating circuit, which, however, would
be depressed by the PC inhibition on the nuclear neurons.
A role of the dentatorubroolivary triangle in motor
learning was suggested by an experiment in which
motor disturbance produced by lesioning the rubrospinal tract that originates from the magnocellular part of
the red nucleus was compensated well only when the
parvocellular part of the red nucleus was intact (279). It
is noted that collaterals of CFs supply excitatory synapses to not only the major nuclear neurons projecting
to the brain stem, but also small GABA-containing nucleoolivary neurons (121). Inferior olive neurons are
thus equipped with both positive feedback via the dentatorubroolivary circuit and negative feedback through
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8. LTD in PC-to-nuclear neuron synapses
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1173
the inhibitory nucleoolivary projection. It is expected
that, while activation of a set of CFs is reinforced by the
positive feedback, concurrent activation of other sets
of CFs would be inhibited by the negative feedback in
the manner of lateral inhibition. Such competition
among sets of CFs has not been reported, but it would
deserve an experimental investigation in connection
with the postulated neural mechanism for choosing an
appropriate microcomplex out of many other with varied parameters (see sect. VI, B5 and C5).
E. As an Internal Model
FIG. 9. Two major forms of motor control systems. A: feedback
control system. g, Signal transfer characteristics of the controller; G,
that of the controlled object; IM, instruction of movement; CM, command signals for movement; AM, actual movement performed. AM becomes close to IM if g is sufficiently large in A, or f(G) becomes
equivalent to an inverse of G in B.
seemingly feed-forward manner is to utilize an internal
loop through a model that simulates the command/movement conversion by the controlled object (forward
model) and thereby predicts the movment to be produced
by the controlled object (Fig. 11). This model was applied
to interpret functional meanings of the cerebrocerebellar
communication loop (223, 227). If the internal loop contains not only dynamic properties of the controlled object
but also the delay time involved in the external feedback,
exactly the same effect as the external feedback from the
actual movement will be reproduced. This is what is done
in an engineering model called Smith Predictor, and
hence Smith Predictor has been proposed as a form of
internal models in the cerebellum (372). The two modes
of control in Figures 10 and 11 should contribute differently to learning of movement, and both may be executed
in combination (171, 229, 276, 557, 558).
A forward model mimics the conversion of command
of a movement in the coordinates of the body to an actual
movement in the coordinates of the workspace, and an
inverse model converts vice versa. When these conver-
FIG. 11. Seemingly feed-forward control system with an internal
feedback through a forward model. AM becomes equivalent to IM if the
signal transfer characteristics of the forward model G⬘ ⫽ G. [From Ito
(232). Copyright 2000 Elsevier Science. Originally modified from Ito
(227).]
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Modern control system theories have been useful in
accurately defining roles played by a microcomplex in
motor control. In the usual design of a control system,
precise control is secured by feedback (Fig. 9A). However, such feedback is not always available in living bodies, and an essential role of the cerebellum appears to
secure precise control without feedback (225, 227, 276).
In a typical feed-forward control (Fig. 9B), the controller
converts instruction for a movement to command signals
that act on the controlled object. The controlled object in
turn converts the command signals to an actual movement. If the instruction/command conversion is inversely
equivalent to the command/movement conversion by the
controlled object, the actual movement becomes equivalent to the instruction (Fig. 9B). This inverse model principle was applied to the control of a robot’s arm (214) and
has been considered as a major mechanism for bodily
motor control. A unique two-degrees-of-freedom adaptive
control system for voluntary movement proposed by Kawato and colleagues (171, 276) combines feedback control by the cerebral cortex with feed-forward control by
the cerebellum (Fig. 10).
Another way of performing a precise control in a
FIG. 10. Two-degrees-of-freedom control system. [From Ito (232).
Copyright 2000 Elsevier Science. Originally modified from Kawato et al.
(276).]
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VI. EXPERIMENTAL EVIDENCE FOR
FUNCTIONAL ROLES OF
LONG-TERM DEPRESSION
The above-presented hypothesis that the microcomplex makes precise feed-forward control possible by
forming an internal model through error-driven LTDbased learning is examined below in the light of available
experimental data. These data were collected from the
three particular viewpoints: 1) error representation by
CFs, 2) involvement of LTD in motor learning, and 3)
behaviors of PCs, in various forms of motor control.
A. Error Representation by CFs
The ways of detecting errors vary, and the errors
represented by CF signals are of varied nature, as reviewed here for various forms of motor learning. In simple situations, CF error signals are derived from sensory
systems detecting a harmful consequence of a wrongly
executed movement (sect. VI, A1 and A2) or monitoring a
deviation of a realized movement from a desired one
(sect. VI, A3 and A4). However, in more complex situations, errors appear to be sensed even before the actual
movement is executed, by comparing the instruction with
a consequence predicted within the central nervous sys-
tem (sect. VI, A4 and A5). The notion of error representation by CFs is expanded to include not only those errors
detected externally through sensory systems but also
those errors derived internally through a neural mechanism for feed-forward control.
1. Errors in flexion reflex and startling
Complex spikes elicited in the paravermal zone of the
cerebellum in response to nociceptive stimuli from the
skin of a finger (140) would inform PCs about the occurrence of errors in the flexion reflex that withdraws the
finger from the noxious stimulus. In awake monkeys startled by sudden loud sounds, complex spike discharges
were evoked in PCs of lobule VI, paramedian lobule, and
dorsal paraflocculus (391). These complex spikes may
reflect errors of the startle response in minimizing the
impact of the sudden loud sounds.
2. Unconditioned stimulus in conditioning
Classical conditioning of the rabbit nictitating membrane/eyelid response (eye blink) can be established by
combining an innocuous stimuli such as a tone as conditioned stimulus (CS) and a nocuous stimulus such as an
air puff to or electrical stimulation around the eye as
unconditioned stimulus (US) (282, 366, 517, 518, 567, 568).
Complex spikes are elicited by corneal stimulation as US
and represent errors in timely eye closure to avoid corneal stimuli. The air puff-induced responses in the dorsal
accessory inferior olive neurons of rabbits were initially
large, but they diminished during acquisition of the eyeblink conditioning (477). Disrupting inhibition of the inferior olive prevented this “blocking” (281). In decerebrate ferrets, electrical skin stimulation of the forelimb as
CS was paired with periocular skin stimulation as US to
form eye-blink conditioning (200). The CS did not inhibit
the occurrence of US-induced CF responses in PCs at the
beginning of training, but it did so in some animals when
conditioned responses became large. The negative feedback via the inhibitory nucleoolivary projection is likely
to mediate the behavioral phenomenon of blocking (sect.
VID2).
3. Retinal slip in ocular movement
PCs in the flocculus of rabbits and cats exhibit complex spike discharges in response to retinal slip (128, 159,
176, 301). Continuous rotation of the visual field upregulated CRF and its mRNAs in the inferior olive, apparently
due to an enhanced retinal slip input (36, 37). PCs in the
monkey’s cerebellar area, which was originally taken as
flocculus, but later redefined as the ventral paraflocculus
(169, 498), exhibited an increased complex spike discharge during smooth pursuit eye movement, representing retinal slip resulting from inadequate tracking (498).
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sions are performed on the dynamic characteristics of the
controlled object such as torque and muscle tension, the
internal model represents forward or inverse dynamics of
the controlled object. When the conversion is performed
on the kinematic properties of the controlled object such
as movement direction and target position, the internal
model represents forward or inverse kinematics of the
controlled object. These internal models may not necessarily be limited to the cerebellum. They may distribute to
various parts of the central nervous system such as spinal
cord, basal ganglia, and cerebral cortex, and the cerebellum may contribute to an important portion of them (473).
Computational potentialities of the cerebellum in
forming such an internal model, either forward or inverse,
within its elaborate neuronal networks by learning have
extensively been explored in recent years. An equation
representing dynamics or kinematics, or their inverse, for
a multi-joint arm, for example, consists of many terms
including mass, inertia, length of segments of the arm, and
viscosity in joints so that analytical solution of the equation requires an enormous amount of computation. A
surprising capability of the Simple Perceptron-like network of the cerebellum has been found to be such that it
quickly forms an internal model for a multi-joint arm
without specific information about individual terms of the
equation, simply by the error-driven LTD-based learning
(275, 472, 473, 558).
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CEREBELLAR LONG-TERM DEPRESSION
1175
cord do not converge onto the same inferior olivary neurons (120), the comparison between the descending and
ascending signals may not directly be made in the inferior
olive as suggested earlier (375, 422).
4. Perturbed posture and locomotion
5. Three types of errors in hand/arm movement
During roll oscillation of frogs, PCs exhibited complex spike discharges, which were larger in the absence of
appropriate compensatory limb movements, suggesting
an error-signaling role of CFs (18). Inferior olive neurons
in the awake cats frequently responded to passive displacement of a limb (168). These responses can be interpreted as signaling errors in a postural adjustment of the
limb (491).
In experiments on decerebrate ferrets, where a bar
that extended into the trajectory of the right forelimb at a
specific phase of the step cycle perturbed locomotion, a
significant increase occurred in the discharges of complex spikes from PCs in lobule V or VI, at times immediately after the perturbation (345). This complex spike
response could represent errors in avoiding perturbation.
During stable treadmill locomotion of decerebrate cats,
complex spike responses of lobule V PCs were only
slightly modulated with a weak increment at the swing
phase of the ipsilateral forelimb, but when the left contralateral forelimb alone was suddenly imposed with a
faster belt velocity, the occurrence of the climbing fiber
discharges was significantly enhanced during the late
swing phase of the ipsilateral forelimb (565). These climbing fiber responses appear to represent errors in interlimb
coordination during locomotion.
CF responses evoked in the C1/C3 zones of lobules V
and VI by elelcrtical stimulation of the superficial radial
nerve of the ipsilateral forelimb displayed modulation of
their sensitivity related to locomotion steps (20). The
largest CF responses occurred overwhelmingly during the
E1 step phase when the limb is extended forward and
down to establish footfall, whereas the smallest responses were seen during the stance phase. This may
suggest that the spinoolivary afferent system is gated to
be most sensitive when the foot is touching down, that is,
when errors tend to happen. In experiments with cats
walking on a horizontal ladder, perturbation by an unexpected 2-cm descent of a stepped-on rung induced complex spike discharges from lobule V PCs, closely timelocked to the onset of rung movement but not its
cessation, which they often preceded (19). Therefore, the
complex spikes appear to compare commands from
higher motor centers via descending connections, with
the activity that these commands evoke in spinal motor
circuits, that is, internal feedback, but not with the peripheral input resulting from the commanded movement.
Because the descending pathways from the motor cortex
and midbrain and the ascending pathways from the spinal
When a monkey was holding a lever driven by torque
motor force against flexion and extension, a shift of the
load at some unpredictable time induced complex spikes
in the intermediate cortex of lobules III through V (170).
These complex spikes occurred just after the load switch
(at 50 –150 ms) and apparently represented errors caused
by a sudden change of the load. Gilbert and Thach (170)
observed that the simple spike discharge decreased reciprocally to the complex spike discharge and remained
decreased after the complex spike discharge had returned
to normal, the early evidence supporting Albus’ (15) hypothesis (sect. IA).
A significant increase in complex spike discharges
was also observed when a monkey, manipulating a stick
to shift a cursor on the screen from a starting box to a
target box, was required to modify the ongoing movement
of placing the cursor within a repositioned target box
(540). This result allows an interpretation that CF signals
occur when the motor state changes and/or during errors
in motor performance. In a paradigm in which a monkey
learned to adapt to a change of the relationship between
the cursor and the hand, complex spike disharges occurred in those trials in which the velocity was inappropriate for the cursor-hand relationship that the animal is
required to learn, suggesting that complex spikes are
associated with velocity-related error signals (416). The
complex spike discharges observed in a multiple-joint
arm-reaching task of monkeys were found to encode distance and/or direction, suggesting that they are spatially
tuned and related to movement kinematics of the arm
(155). This observation is consistent with the hypothesis
of error representation by complex spikes, because in this
experiment the monkey controls kinematic properties of
a multiple joint arm.
However, complex spike discharges were found to
occur in various phases of hand/arm movements, often
unrelated to feedback of consequences from the performed movement (415). In a visually triggered tracking
movement of the wrist by monkeys, the firing rate of
complex spikes increased immediately following electromyography activity in prime mover muscles, before the
beginning of the actual movement (358). The timing of
complex spike discharges was analyzed in detail in monkeys performing short-lasting reaching hand/arm movements (286). The monkeys saw the hand and the target
before and after the movements, but the reaching movements were performed without visual feedback. When
monkeys moved the hand to touch a visual target that
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In the ocular following movement elicited by slow whole
visual field movement, PCs in the monkey’s ventral paraflocculus showed a modulation pattern of complex spike
discharges correlated with retinal slip (290).
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appeared at a random location on a screen, complex
spikes were shown to occur in three phases (first, second,
and third responses) (Fig. 12). The third response falling
after the end of the reaching movements apparently represents visually perceived deviations between the target
and the reached finger position, but the first and second
responses appear too early to be interpreted similarly.
Kawato et al. (276) postulated, as the most plausible
possibility, that errors are derived from the output of the
cerebral cortex, which also generate the motor commands to the hand/arm system (feedback-error learning)
(Figs. 10 and 11). In this design, the discrepancy between
the instructed target position and the hand position predicted by an internal forward model in the cerebellum is
fed to the inferior olive via the cerebral cortex (Fig. 11).
This may explain the second complex spike response in
the reaching movement (286).
The earliest component of complex spike discharges
can also be explained by the feedback-error learning
scheme. When the monkey initiates the reaching in dark,
the cerebral cortex is driven by the instruction of movement toward the target position, and this instruction is fed
to the inferior olive via the cerebral cortex (Figs. 10 and
11). If the instruction represents the discrepancy between
the initial set position of the hand and the visually instructed target position, it implies in a sense an error. The
initial set error, as it may be called, might be referred to
if the monkey learned to shift the initial set position of the
hand closer to the target zones before initiating the reach,
but this was prevented in the experiment. Or, the initial
set error might represent the discrepancy between the
target position actually viewed and that which the monkey anticipated from preceding experiences. Such an error might be referred to if the monkey learned to reach a
target repeatedly appearing at the same position, but this
learning was also prevented by randomizing the target
position. Therefore, the earliest complex spike discharges
would play no roles in the given situation where learning
is prevented. A computer simulation of learning reaching
movement adopting the feedback-error learning reproduced complex spike discharges in two phases: the early
response locked to movement onset, which was always
present, and the later response, which disappeared after
learning (475). Because the learning was stable and maintained, the early CF response is considered as inevitable,
but playing no significant roles in performing the given
motor task.
B. Involvement of LTD in Motor Learning
There are numerous data of lesion experiments using
surgical ablation or application of a toxic dose of amino
acids to the cerebellum. However, this section mainly
focuses on recent data obtained by pharmacological or
genetic manipulation of LTD, which has been made possible due to recent advances in our knowledge of signal
trransduction in LTD (sects. III and IV).
1. Adaptation in ocular movement
VOR, producing eye movement compensatory for
head movement, is adaptively enhanced or depressed under persistent vestibular-visual mismatching conditions
(172, 242, 243, 448). The flocculus hypothesis (226) that
the VOR adaptation occurs due to LTD-based learning in
the flocculus is supported by the following observations.
1) VOR adaptation was blocked by superfusing the flocculus of rabbits and monkeys with a NO scavenger, hemoglobin, which should have deprived NO required for
LTD induction (398). 2) Injection of an inhibitor of NOS
into the goldfish cerebellum also inhibited the adaptive
increase of VOR gain (318). 3) Transgenic mice that selectively express the pseudosubstrate PKC inhibitor, PKC-
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FIG. 12. Climbing fiber responses associated with a short-lasting
reaching movement with hand and arm. A: sequential events in the
reaching task. When a target beam appears on the screen, the monkey
releases the button and touches the target on the screen, without
viewing the moving hand. Then, liquid-crystal shutters are opened for
300 ms, allowing the monkey to view the hand, and then closed. B:
information transmission rate (Ir), which reflects the firing frequency of
complex spikes and the predictive information associated with the
occurrence of complex spikes during the time window of 100 ms. Curve
1 with a peak at the beginning of the reaching movement shows Ir values
encoding the absolute destination of the reach. Curve 2/3 has two peaks
at the end of the short-lasting movements encoding the relative errors.
[Modified from Kitazawa et al. (286).]
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CEREBELLAR LONG-TERM DEPRESSION
2. Eye-blink conditioning
The microcomplex involved in eye-blink conditioning
contains HVI lobule cortex (C1 and C3 zones), an anterior
part of the interpositus nucleus and the medial parts of
rostral dorsal accessory olive, since lesions in these regions disrupt conditioned responses (306, 307, 567–569).
Reversible inactivation of the anterior part of the interpositus nucleus by local injection of muscimol prevented
the acquisition of conditioned responses (300) as well as
its extinction (441). Eye-blink conditioning is significantly
impaired in Purkinje cell degeneration (pcd) mutant mice
(89).
In rabbit cerebellar area HVI, an increase of membrane-bound PKC was detected after eye-blink conditioning (150), which could be related to LTD (sect. IVC1).
Those rabbits given a NOS inhibitor, which blocks LTD
induction (sect. IIIA2), exhibited learning deficits in the
conditioned eye-blink response (85). GFAP-deficient mutant mice showed loss of LTD (sect. IVD3) and also impaired eye-blink conditioning (482). Injection of an IGF-I
antisense oligonucleotide in the inferior olive, which re-
duces IGF-I levels in the cerebellum (sect. IIIA5), blocked
conditioned eye-blink learning in freely moving rats (83).
The fact that some conditioned responses remain
after cortical lesions or PC degeneration raises the possibility that a portion of memory trace is retained in cerebellar nuclei or brain stem (444). However, when the
eye-blinking evoked from the conditioning stimulation of
the arm skin was reproduced by direct stimulation of the
cerebellar peduncle, the latency of the conditioned responses suggested signal transfer via the cerebellar cortex, but not via the nucleus (202). Furthermore, a unique
memory role of the cerebellar cortex is indicated by the
finding that cerebellar cortical lesions specifically disrupted the timing of conditioned eyelid responses acquired by learning, and left responses that peaked inappropriately at very short latencies (366, 430). LTD-based
learning in the cerebellar cortex may account for the
well-timed conditioned responses, while the input nonspecific enhancement of excitability in nuclear neurons
(see sect. VC7) may be responsible for the untimely conditioned responses that appear after cortical lesioning.
3. Adaptation in posture and locomotion
Compensation of the impaired righting response by
unilateral lesion of the vestibular organ has been studied
as a type of learning in the cerebellum. The compensation
was retarded in mutant mice deficient in ␦2-protein (158),
consistent with the loss of LTD in this mutant (269). The
behavioral recovery from unilateral labyrinthectomy in
rats was accompanied by asymmetric expression of
PKC-␣, -␥, and -␦ isoforms in the flocculonodular lobe
with a regionally selective increase in the number of
PKC-immunopositive PCs contralateral to the lesion
(175). This asymmetry occurred within 6 h after the labyrinthectomy and was resolved to the control, symmetric
pattern within 24 h. The compensation was retarded in
the rats after intracerebroventricular application of PKC
inhibitors (33), consistent with the requirement of PKC in
LTD induction (sect. IVC1).
When a decerebrate cat walking on a treadmill experienced sudden increase in the speed of the running belt
only under the left forelimb, regular stable locomotion
was restored in 50 –100 steps. Injection of a NOS inhibitor
into the lobule V vermis blocked this adaptation, consistent with the hypothesis that LTD induction is a major
mechanism for cerebellar adaptation (564). mGluR1-deficient mice walking on a treadmill exhibited an abnormally
dispersed locomotor cycle of two limbs, which were
sharply distributed around 180° in wild-type mice, and did
not adapt to an increase of the belt velocity, whereas
wild-type mice progressively decreased step cycle duration (220). These signs of impaired interlimb coordination
in locomotion diminished when the mGluR1 deficiency
was rescued in the cerebellum.
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[19O31], in PCs lacked the VOR adaptation consistent
with the loss of LTD induction in cerebellar slices obtained from these mice (118). In testing VOR adaptation,
a caution is needed to avoid the mouse strain 129/sv
because of its abnormally low VOR gain, while C57BL/6
has a normal VOR gain (273).
Whether the memory trace for VOR adaptation is
eventually formed in the cerebellar cortex or the nucleus,
or even in the brain stem is still controversial (444).
Application of lidocaine to the goldfish cerebellum
through a microdialysis probe abolished the VOR adaptation attained by a few hour stimulation, indicating that the
memory for this adaptation, at least for the initial few
hours, is located in the cerebellar cortex (369).
Continued rotation of the visual field around a stationary rabbit induced an increase in the optokinetic eye
movement response (OKR) in 1 h (396, 397). 3-AP-induced
depletion of CFs abolished OKR adaptation in mice (272),
and nNOS-deficient mice lacked OKR adaptation (273).
Fyn is a member of the src subfamily of the genes encoding nonreceptor PTKs (357), which have been implicated
in LTD induction (sect. IVC3), but Fyn-deficient mice exhibited normal adaptability of OKR (287). Probably, some
other member(s) of the src subfamily is involved in LTD.
When a monkey making a smooth pursuit eye movement is repeatedly faced with a sudden increase in the
velocity of the moving target, it adapted to start the
pursuit with an increased velocity. Subdural applications
of NO scavenger or NOS inhibitor to the paraflocculusflocculus scarcely affected the smooth pursuit, but markedly depressed its adaptation, suggesting that cerebellar
LTD underlies the adaptation of smooth pursuit (400).
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Volume 81
1. Cerebellar dysfunction in mutant mice
Cellular Abnormality
Targetted
Genes
mGluR1
Eye-blink
conditioning
Motor
coordination
CF
Abs
Multi
Abn
Abs
Abs
Abs
Retained
Retained
Multi
Multi
Abn
Abn
Abn
Abn
Abn
Abn
Abn
Norm?
Norm?
Abs
Abs
MF/GA/PC
VOR/OKR
adaptation
LTD
Abs
Multi
Abn
Multi
(Multi)
Single
Multi
Abn
Abn
Abs
Reference Nos.
6, 100, 220,
259, 321
209, 269
381, 414
273, 381
86
428
260
252
482
118
MF/GA/PC, mossy fiber (MF)-to-axons of granule cells (GA)-to-Purkinje cell (PC) transmission; abs, absent; abn, abnormal; multi, multiple
innervation of PCs by climbing fibers (CFs); (multi), possible multiple innervation; single, normal one-to-one innervation of PCs by CFs; norm?,
seemingly normal; nNOS, neuronal nitric oxide synthase; PKC, protein kinase C; GFAP, glial fibrillary acidic protein.
4. Motor coordination
Coordination of complex movements has been regarded as a major function of the cerebellum (516). In
experiments on mice, motor coordination is tested by
observation of locomotor ataxia, rope climbing, running
on an elevated runway with low obstacles, and evaluated
by measuring the time during which an animal can remain
on a horizontally placed rotating rod. Significant shortening of the staying time has been reported in a majority of
the 10 types of gene-manipulated mice (Table 1). It is to
be noted that nNOS-deficient mice show no obvious motor discoordination during daytime, but they exhibit peculiar motor discoordination during night (299).
Six of the eight types of gene-manipulated mice
showing motor discoordination were tested for LTD induction in cerebellar slices obtained from them. Four
types, namely, mGluR1- (6, 100), GluR␦2- (209, 269), G␣q(381) and nNOS-deficient (316) mice lacked LTD; however, the other two, namely, PKC-␥- (86) and mGluR4deficient (428) mice retained LTD. Hence, lack of LTD is
not the sole cause for motor discoordination. PKC-␥deficient mice (258) exhibited persistent multiple innervation of PCs by CFs, which, even though LTD is retained,
is expected to impair the function of cerebellar neuronal
circuit due to loss of the microzone specificity of CF
innervation (sect. V, A2 and B3, and Fig. 8). Multiple CF
innervation was also found in the three mutants lacking
LTD [mGluR1 (259, 311), GluR␦2 (269), G␣q (414)], and
hence which of LTD or multiple CF innervation is the
major cause for motor discoordination is unclear. The
abnormal transmission in GA-PC synapses found in the
mGluR4-deficient mice (sect. IIB1) could explain dysfunction of the cerebellar neuronal circuit and consequently
motor discoordination in this mutant despite the presence
of LTD. LTD induction in PLC-␤4-deficient mice has not
been tested, but the occurrence of multiple CF innerva-
tion (260) in them explains motor discoordination. NR2A/
NR2C-deficient mice (252) are likely to develop multiple
CF innervation of PCs, since wild-type mice develop it
after application of NMDA receptor antagonists to the
cerebellar surface in vivo (253, 439).
Because genes are manipulated all over the body in
these mutants, specific relationships of the observed motor discoordination to the cerebellum may be questioned;
it might arise from dysfunction of the cerebral cortex,
basal ganglia, or spinal cord. This question was addressed
in the experiment in which mGluR1 deficiency was rescued in the cerebellum (220). It was remarkable that the
rescue-induced regression of multiple CF innervation and
recovery of LTD paralleled improvement of motor coordination (220).
However, GFAP-deficient mice were reported to exhibit motor coordination indistiguishable from a wild type
of mice despite the lack of LTD (482). PKC-inhibitortransfected mice also were reported to exhibit seemingly
normal motor coordination in the absence of LTD and in
the presence of multiple CF innervation (118). These
observations are difficult to reconcile with the hypothesis
of cerebellar learning, but the author points out the fact
that, compared with ocular adaptation, eye-blink conditioning, adaptive locomotion or hand/arm movement, motor coordination has been investigated only poorly in
terms of responsible neuronal circuits as well as quantitative evaluation methods of the motor deficiency. Impairment of eye-blink conditioning in GFAP-deficient mice
(482) and loss of VOR adaptation in PKC-inhibitor-transfected mice (118) appears to be a more reliable index for
cerebellar dysfunction (see also sect. VID6).
5. Adaptation in hand/arm movement
To throw balls of clay at a visual target while wearing
wedge prism spectacles, normal subjects initially threw in
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GluR␦2
G␣q
nNOS
PKC-␥
mGluR4
PLC-␤2
NR2A/NR2C
GFAP
PKC inhibitor
Behavioral Abnormality
July 2001
CEREBELLAR LONG-TERM DEPRESSION
C. Functional Representation of PC Activities
The assumption that each microcomplex plays a
unique functional role in neural control system functions
is tested here based on the data obtained by recording
simple spikes that are the major output signals of PCs.
1. HVI area in eye-blink conditioning
After training for eye-blink conditioning in rabbits,
some PCs, mostly sampled from HVI lobule, exhibited a
transient decrease of their simple spike discharges in
response to the conditioning stimuli (50, 200, 518). This
decrease occurred at about the time when anterior interpositus neurons discharged to induce conditioned responses. This observation can be explained based on the
microcomplex model if there is a delay line mechanism
converting the temporal pattern of the CS-induced activation in a set of MFs into a spatial pattern of GAs each of
which discharges at varied time during the conditioned
stimulation (387). Although these GAs converge onto a
PC, LTD would depress only those GA-PC synapses conjunctively activated with the CF signals, and hence PCs
would be deactivated around the time of unconditioned
stimulation. The possibility that such temporospatial conversion occurs in the brain stem is unlikely because single
pulse stimuli directly given to MFs stimuli can reproduce
eye-blink conditioning acquired by paired forelimb and
periocular stimulation (202). A likely possibility is that the
temporospatial conversion occurs in the MF-GA circuit
including Golgi cells (156).
2. Flocculus in VOR adaptation
During sinusoidal whole body rotation of a rabbit or
monkey in the horizontal plane, PCs in the microzone
connected to the horizontal VOR (H zone) exhibited a
significant modulation of simple spike discharges in relationship with the head velocity on the horizontal plane
(166, 544). The pattern of simple spike discharges from
rabbit flocculus PCs changes in parallel with adaptation
of VOR in the manner that suggests a causal relationship
between the former and the latter (128, 397, 544). Changes
correlated with OKR adaptation were also found in PCs of
the rabbit flocculus (396).
3. Ventral paraflocculus in ocular following
When a monkey moves its eyes following a movement of the whole visual field (ocular following), simple
spike discharges in PCs of the ventral paraflocculus were
modulated with a pattern, which matches well with the
inverse dynamics of the eyeball (486). The inverse dynamics of the eyeball are represented by an equation that
contains terms of eye acceleration, eye velocity, and eye
position. This observation can be explained based on the
control system design of Figure 9B. It was also found that
the simple spike modulation was a mirror image of the
pattern of complex spike discharges (290). Apparently,
the inverse dynamics pattern of simple spike modulation
is formed through LTD-based learning. The retinal slip
caused by deviations between the movement of visual
surroundings and that of the eyes contains information
about the dynamics of the eyeball, which is conveyed by
CFs to shape the behavior of PCs by LTD.
4. HV/HVI areas in arm movement
When a monkey makes a visuomotor arm tracking in
a two-dimensional workspace, simple spike discharges in
PCs sampled from intermediate and hemispheric cortex
of V and VI (HV and HVI) were modulated in relation with
direction, distance, or target location (154), most strongly
at specific combinations of direction and speed, suggesting that they had a preferred velocity (97). These observations match the kinematics representation found with
complex spikes (155) and are consistent with the hypothesis that the cerebellum forms a kinematics model of the
arm (sect. VE).
5. Internal model for a new tool
A recent functional magnetic resonance imaging
(fMRI) study on a human subject revealed a persistent
change of local blood circulation in the cerebellum, which
is presumed to represent an internal model postulated in
Figures 10 and 11 (221). While a subject manipulated a
computer mouse to follow a moving small square target
with a small cross-hair cursor on a screen, the position of
the cursor was rotated 120° around the center of the
screen to provide a novel mouse condition. In the first
session, large regions of the cerebellum were significantly
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the direction of prism-bent gaze, but with 10 –30 repeated
throws adapted to hit the target. Patients with focal olivocerebellar lesions had impaired or absent prism adaptation, suggesting that climbing fibers play a role for this
adaptation (361). Monkeys learn to reach and touch a
target either with or without wearing the “learned” prism
spectacles, thus acquiring and storing two gaze-reach calibrations (360). Martin et al. (360) found that, when the
posterior cerebellar cortex was inactivated by lidocaine
injections, the monkey failed to perform short-term adaptation to novel prisms and lost the learned prism adjustment. Motor memory may be located in the cerebellar
cortex, or it may be accessed through the cerebellar
cortex. The quick switching between the two gaze-reach
calibrations raises an interesting possibility that a neural
mechanism exists, probably outside of the cerebellum, for
selecting an appropriate one out of a number of microzones specialized for the same movement but with different parameters (see sect. IVD5).
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D. Consistency of LTD With Learning
While evidence accumulates in favor of the hypothesis that LTD is the core process of learning mechanisms in
the cerebellum, as reviewed in section VI, A–C, a number
of criticisms against the hypothesis and other different
views have been presented. Even though it may require
additional data before we clarify the entire situation for
the microcomplex hypothesis on experimental bases, current major objections can be debated on the basis of
already available data.
1. Timing between CF and GA signals
In actual motor control situations, it may happen that
CF error signals arrive at PCs well after activation of
GA-PC synapses so that no CF/GA conjunction could
occur. However, the GA-CF temporal relationship for LTD
induction is broadly tuned (88, 265), and LTD occurs even
if CF signals reach PCs after GA signals (468, 538) (sect.
IIA4). A basis for explaining the “credit assignment” has
been derived from knowledge of often long-lasting signal
transduction processes underlying LTD (sect. IVF). It has
also become evident that CF error signals are derived not
only from the final consequence of the operation of a
neural system involving the microzone, but also from a
prediction made within the central nervous system before
completion of the operation (sect. VE).
2. Spontaneous GA and CF activities
Provided that each granule cell discharges spontaneously at 10 –50 Hz, there will be a frequent chance of
conjunctive activation of GAs with spontaneous CF impulses so that all GA synapses in a PC could be depressed
in a relatively short time (336). However, LTD induction
has a prominent frequency dependence (sect. IIA4) so that
it would not happen with slow, irregular background
discharges of CFs.
3. Reciprocal modulation
Simple spikes and complex spikes are not always
modulated reciprocally to each other, even though this is
expected to occur after LTD-based learning (491, 492).
Reciprocal modulation has been observed typically in
monkey ventral paraflocculus during ocular following
(290) and also in rabbit flocculus during head rotation in
the light (122). However, part (11 of 43) of flocculus PCs
tested by rotation in dark showed parallel modulation of
simple and complex spikes instead of reciprocal modulation (122). It is not surprising because the simple spike
modulation of flocculus PCs reflects a summed effect of
excitation mediated by GAs and inhibition mediated by
basket and stellate cells (379). Even if LTD depresses
GA-PC synapses, the inhibition-dependent component of
modulation will remain unchanged because LTD does not
influence the MF-induced inhibition in PCs (241). Another
seeming contradiction was that when PCs discharged
complex spikes at the onset of monkey’s wrist tacking
movements, a slightly more than one-half of the PCs also
exhibited an increase of simple spike discharges (358).
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activated, but the extent of activation decreased during
repeated test trials in parallel with a reduction in the
tracking errors. Eventually, certain subregions (near the
posterior superior fissure) continued to be activated. This
remaining restricted activity may represent an internal
model formed during the repeated test trials, which implies a novel relationship between the cursor movement
and the mouse movement. Because the subject can switch
between the old and novel mice quickly, this also suggests
a neural mechanism for selecting an appropriate one out
of many internal models for various mouse situations (see
sects. VD3 and VIB3).
When we consider how the activity detected by fMRI
in the cerebellum is related to LTD, it should be realized
that diverse chemical reactions underlie the induction of
LTD, including the release of NO (sect. IIIA2), which has a
well-known action of relaxing blood capillaries (231).
Actually, the cerebral blood flow measured directly on the
surface of the cerebellum, using laser-Doppler flowmetry,
increased in relation with electric stimulation of PFs and
was attenuated by application of a NOS inhibitor (14).
Because picrotoxin did not affect the cerebral blood flow,
inhibitory synaptic activity did not appear to contribute to
the observed cerebral blood flow changes. Therefore, an
increase of cerebral blood flow in the cerebellar cortex is
likely to reflect an increased activity in GAs.
One may suppose that, at the beginning of motor
learning, the cerebral cortex sends MF signals via pontine
nuclei widely to the cerebellum so that GAs are activated
in a wide area of the cerebellum, as occurs in the early
phase of learning (221). In this early phase, there could be
little output from cerebellar nuclei because of dominant
PC inhibition. When a microcomplex receives error signals conveyed by CFs during repeated trials of the movement, LTD will develop in the microzone, and consequently its nuclear output will be released from PC
inhibition. If the released nuclear output contributes to
improve the movement, the cerebral cortex would reduce
exploratory signals to the cerebellum, as represented by
the subsidence of activation in the cerebellum (221).
Then, how does GA activity grow and is maintained only
in that particular microcomplex, as seen by Imamizu et al.
(221)? The author pays a special attention to the nucleocortical projection (Fig. 6), which may act to maintain the
high activity of GAs in the microzone connected to the
nuclear neurons released from PC inhibition during learning (sect. VB2).
Volume 81
July 2001
CEREBELLAR LONG-TERM DEPRESSION
Since, however, this experiment was made after the monkeys well learned the movement, the observed simple
spike discharge might be a residue remaining after LTD
had already shaped it from the original, probably larger
response. It might not undergo a further depression in the
postlearning phase where the complex spikes were driven
by wrist tracking at a very low rate.
4. Natural stimulus-evoked CFs
5. Opposing process to LTD
LTD may be incomplete as a mechanism for learning
because of the lack of a known opposing process (336).
Without such a process, all GA-PC synapses could eventually be depressed. The major assumption adopted in
neuronal network models of the microcomplex is that
those GA-PC synapses escaping conjunctive activation
with CFs are potentiated (156), or that the total effect of
GA-derived synapses in each PC is kept constant by nonspeific occurrence of LTP (475). In reality, presynaptic
LTP occurs in GA synapses activated without conjunction
with CFs (sect. VC3). It counteracts LTD in terms of
synaptic efficacy so that the combination of LTD and LTP
provides a complete learning mechanism from computational viewpoints. Whether there is any mechanism that
counteracts LTD at molecular levels is still an open question.
6. Discrepancy in motor discoordination
Behavioral disturbances observed in various types of
gene-manipulated mice are not always correlated to LTD
(336). Although lack of LTD is well associated with impairment of ocular movement adaptation (sect. VIB) (230)
and eye-blink conditioning (sect. VIB2) (282, 366), LTD is
less correlated with motor discoordination. LTD is
present in two of the six types of gene-manipulated mice
exhibiting motor discoordination and tested for LTD induction (Table 1). This may be because motor discoordination can be impaired by various causes, not only lack of
LTD but also multiple CF innervation or abnormal MFGA-PC transmission. However, the two cases in which
motor coordination was indistinguishable from wild-type
mice despite the lack of LTD (Table 1) are difficult to
reconcile, and further investigation is required to find the
reason for this discrepancy. It is necessary to identify
neuronal circuits responsible for motor coordination and
to introduce sensitive methods for evaluating motor disturbances under various test conditions. It is to be recalled that nNOS-deficient mice show no obvious motor
discoordination during daytime, but they exhibit peculiar
motor discoordination during the night (299).
7. Clock function of CFs
An alternative hypothetical role of the CFs is that
they provide a clock for movement control (336, 341).
This view is based on two lines of evidence that, under the
influences of harmaline, complex spikes discharge rhythmically at a rate ⬃10 Hz (303, 340) and that, in slice
conditions, inferior olive neurons exhibit a marked oscillation in membrane potentials (342). The clock hypothesis, however, is not consistent with the results of recording from PCs in awake behaving monkeys, which did not
reveal clocklike discharge patterns of complex spikes
(277, 278). A computer simulation study suggests an interesting possibility that electrical coupling between inferior olive neurons through gap junction acts to either
synchronize or desynchronize coupled inferior olive cells
depending on the coupling strength (474).
8. CF activity and licking
Licking is skilled tongue movements repeated in a
form of a series of rhythmic trains. In a certain area of rat
cerebellar cortex, PCs were found to discharge complex
spikes rhythmically and time-locked to movement at
about the time when the tongue was fully extended, some
PCs firing in synchrony with each other (550). These
complex spikes do not represent consequences of movement, since they are unaffected by deafferentation of the
oral or perioral structures. Welsh et al. (550) suggest that
the complex spike activities are transferred to cerebellar
nuclear neurons via PC axons and eventually aid tongue
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Conjunction of natural stimulus-evoked simple
spikes with spontaneously occurring complex spikes in
cat cerebellum did not induce LTD (58). When a small
flexion of a forepaw wrist was applied to evoke simple
spike responses (either increase or decrease of the discharge rates) in PCs 20 –70 ms after spontaneously arising
complex spikes, the simple spikes exhibited a short-term
facilitation rather than a long-lasting depression (131).
However, slow, irregular spontaneous discharges of complex spikes and also the occurrence of inhibition in PCs
after the forepaw flexion may account for the failure of
LTD induction. It was also reported that when the forepaw flexion evoked complex spikes in combination with
simples spikes, the simple spike responses were accentuated compared with those trials where no complex spikes
were evoked (132). However, the effects of complex
spikes upon simple spike responses were estimated by
constructing poststimulus histograms during 39 –53 trials,
which do not seem to be sufficiently large in number for
inducing LTD. The short-term facilitation observed in the
simple spike responses combined with complex spikes
was attributed to a change of responsiveness of PCs to
MF inputs, but a possibility might remain that it was due
to a change of transmission efficacy in the pathways
relaying cutaneous and proprioceptive signals to PCs.
1181
1182
MASAO ITO
motoneurons that execute movement. Another possibility
may remain, however, that complex spikes reflect discrepancies between instructions for licking movements
and the internal feedback, as appears to be the cases in
perturbed locomotion (sect. VIA4) and hand/arm movement (sect. VIA5).
9. Protective action of LTD
LTD may function for avoiding overexcitation of PCs
(113) or Ca2⫹-mediated excitotoxicity (336). These possibilities are, however, not exclusive to the memory and
learning function considered in this review.
Volume 81
within the elaborate neuronal networks of the cerebellum
after error-driven LTD-based learning.
The two research directions, one to extend LTD studies to reveal memory mechanisms of the cerebellum and
the other to extend from motor learning to implicit learning in general, are mutually dependent and should be
promoted together. Future studies of the cerebellum are
thus expected to lead us to understanding of the entire
mechanisms and functional roles of the cerebellum in
implicit memory and learning in general, which in fact
govern a large part of our life.
VII. CONCLUSION
Owing to the great efforts made during the past two
decades, our understanding of the mechanisms of LTD
and its functional roles has remarkably deepened. However, more data need to be accumulated for testing hypotheses, and hypotheses need to be more refined to
match the actual data. Toward the final goal of understanding learning mechanisms of the cerebellum, the following questions are to be addressed.
How is LTD eventually converted to permanent memory? Efforts are required to extend the observation time
for LTD further (sect. IID) to reveal persistent changes in
either molecular or cellular structures at the synaptic
sites. Investigation of gene regulatory mechanisms for
LTD will be of essential importance. A possibility exists
that LTD as functional depression is consolidated as a
structural change in synaptic contacts and spines. Even
though evidence is available for the dependence of spine
density in PC dendrites on afferent input activities (67),
there is no evidence yet showing morphological changes
correlated to LTD. The functional architecture of the
microcomplex including accessory circuits also needs to
be analyzed further to understand the operational principles of the entire cerebellar circuits.
Can the microcomplex concept be expanded to apply
beyond motor learning to implicit learning in general? It
has been applied to various physical functions including
reflexes, compound movements (such as locomotion and
saccade), animal behavior, and voluntary movement, and
an obvious next target of cerebellar research is to determine the cerebellar contribution to certain mental functions such as cognition, language, and thought, as has
been suggested based on an analogy with movement (229,
233). Studies on human subjects are becoming increasingly important, and requirements for new research technologies applicable to humans will greatly increase. A
profound central problem in these studies is to find out,
both experimentally and theoretically, how internal models for mental functions are formed and represented
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