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Facilitation, augmentation and potentiation
at central synapses
Alex M. Thomson
Release probability (P) appears to be a major factor that influences the pattern of transmitter
release. At cortical pyramidal axon inputs onto different classes of target cells, very different
release patterns are observed, patterns that correlate with release probability. Simplistically,
‘low P’ synapses display facilitation and augmentation, whereas ‘high P’ synapses supplied by the
same axon exhibit paired-pulse and frequency-dependent depression. Different combinations of
factors probably contribute to release probability at different terminals, during development and
under different experimental conditions. The recent advances made by molecular biological
studies of the release machinery do, however, provide candidate proteins and protein–protein
interactions whose differential distributions might be important factors in determining the
patterns of transmitter release.
Trends Neurosci. (2000) 23, 305–312
Increases in transmitter release by successive impulses
in a train fall into two categories, those which act over
relatively brief intervals (facilitation) and those which
are small, but accumulate significantly during prolonged
stimulation, augmentation and potentiation.
Different degrees of facilitation are inversely related
to different (unfacilitated) values of P.
McLachlin (1978)1.
A
LL neocortical and hippocampal synapses studied
in detail to date can exhibit facilitation, provided
the appropriate experimental conditions apply, although facilitation is most clearly apparent when the
release probability (P) is relatively low. When P is high,
the several forms of presynaptic depression dominate. The two slower components of presynaptic enhancement, augmentation and potentiation, are readily demonstrated at cortical synaptic connections that
have low P values under control conditions. Their functional expression is more difficult to demonstrate at
connections with high values of P, where depression
dominates.
Defining the binomial parameter P
Whether or not the Ca21 that enters the nerve terminal during any one action potential (AP) releases a
given fusion-competent vesicle2–10 (Box 1; Fig. 1) is
dependent on several factors. These factors might not
be identical at all contributory release sites, or even
from AP to AP. Because repetitive release involves an
often non-stationary population of all-or-none events,
P is just as difficult to define in a precise and unambiguous way as n is (the number of points from which
release could occur). Any definition of P also depends
upon the definition of n used. If functional n is taken
to represent the number of docked, unrestrained and
fusion-competent vesicles (as it is in this article), P
becomes the probability that each competent vesicle
will be released by a single AP. In this case, a refractory
release site16 (Box 2) that has recently discharged a
vesicle, will not contribute to n and will have no effect
0166-2236/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
on P. If, however, the definition of n includes all
release sites, whatever their recent release history,
those that are refractory will also contribute to n.
Estimates of P will then include sites with a transiently
zero probability. Thus, when short-term synaptic plasticity is under discussion, whether it is n or P that is
considered to have changed depends on the definitions and models applied. These are, however, useful
terms for discussion, provided the definitions remain
consistent.
Factors that might influence P
The factor that determines the very different values
of P (0.01 to 0.9) at different release sites could simply
be a difference in local Ca21-buffering or affinity, or
both. At a ‘high P’ synapse, for example, some Ca21binding sites might already be occupied at rest, increasing affinity at other binding sites and reducing
the requirement for additional Ca21 to enter during an
AP (Box 3). Alternatively, the AP might have different
characteristics at different terminals, since the presynaptic Ca21 current is very sensitive to the degree and
duration of depolarization. On the other hand, there
might be a differential expression of the proposed
Ca21 sensor, the synaptotagmins4,7 with different affinities for Ca21. With four cooperative Ca21-binding
sites associated with the release machinery, a twofold
change in the Ca21-sensor association time constant is
predicted to result in a 16-fold change in the probability of exocytosis17. Alternatively, cysteine string proteins (CSPs), which promote Ca21 channel opening at
release sites, might be differentially expressed; the
degree of incorporation of Ca21 channels into the release machinery might vary; or one of the later stages
in the development of fusion competence might be
differentially regulated by phosphorylation.
The shape of the AP, and the number, location and
properties of the Ca21 channels will determine the shape
and size of the local Ca21 transient. Providing the Ca21 influx during an AP is not very much more than is required
to saturate the four Ca21-binding sites, modification of
PII: S0166-2236(00)01580-0
TINS Vol. 23, No. 7, 2000
Alex M. Thomson
is at the Dept of
Physiology, Royal
Free and
University College
Medical School,
London,
UK NW3 2PF.
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Box 1. Ca21 influx initiates fast, synchronous transmitter release
A fully fusion-competent synaptic vesiclea–f at a fast central synapse
responds extremely rapidly [in under 200 ms (Ref. g), with recent
estimates as low as 30–60 ms] to a local influx of Ca21 during the
action potential (AP). It fuses completely with the plasma membrane,
disgorging its contents into the synaptic cleft (see Refs e,h,i for
reviews). The very rapidity of this step indicates that many of the
molecular interactions involved in vesicle docking and the acquisition
of fusion competence might have happened long before that AP
reaches the terminal. If the local Ca21 signal is brief, it helps ensure
near synchronous release of transmitter from all activated release
sites. One intriguing observation commonly made when mature fast
central synaptic connections are studied at physiological temperatures,
is the impressive degree of synchrony in the release from the several
synapses that constitute each connection (despite the disparate and
often convoluted paths that the different axonal branches supplying them have taken en route, and the often very slow conduction
velocities of these unmyelinated local collaterals). If the temporal
spike-code carries useful information, synchronous release of transmitter would be an important component of its transfer and one
that appears to be ensured by more than one mechanism.
Calcium microdomains
Studies using the Ca21-reporter molecule, aequorin, whose very
low binding coefficient allows rapid binding and unbinding, culminated in the proposal that transient Ca21 microdomains trigger
release from sites very close to the point of Ca21 entryj–l. The Ca21
that triggers release is proposed to enter through a small number of
Ca21 channels close to the release site and, for a brief time, the
[Ca21] in that ‘microdomain’ is very high. Studies in which Ca21
channels in the presynaptic membrane of the calyx of Held were
recorded directly, with simultaneous detection of transmitter
release, indicated that as few as 200 Ca21 ions and the opening of a
single Ca21 channel could initiate transmitter releasem (see Refs n,o
for further discussion). The microdomain hypothesis is further supported by immuno–precipitation experiments in which v-conotoxin GIVA-labelled N-type Ca21 channels were found to precipitate
with synaptotagmin and syntaxinp; with synaptotagminq; and with
neurexin, synaptotagmin and syntaxinr. Both N- and P/Q-type
channels precipitated with syntaxin, 25 kD synaptosomal-associated protein (SNAP25), synaptobrevin (VAMP), and with synaptotagmin I and II (see Ref. d for review).
References
a Jahn, R. and Südhof, T.C. (1993) Synaptic vesicle traffic: rush hour at
the nerve terminal. J. Neurochem. 61, 12–21
b Butz, S. et al. (1998) A tripartite protein complex with the potential to
couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94,
773–782
c Geppert, M. and Südhof, T.C. (1998) RAB3 and synaptotagmin: The yin
and yang of synaptic membrane fusion. Annu. Rev. Neurosci. 21, 75–95
d Seagar, M. et al. (1999) Interactions between proteins implicated in exocytosis and voltage-gated calcium channels. Philos. Trans. R. Soc. London
Ser. B 354, 289–297
e Fernandez–Chacon, R. and Südhof, T.C. (1999) Genetics of synaptic
vesicle function: Toward the complete functional anatomy of an
organelle. Annu. Rev. Physiol. 61, 753–776
f Benfenati, F. et al. (1999) Protein–protein interactions and protein modules in the control of transmitter release. Philos. Trans. R. Soc. London
Ser. B 354, 243–257
g Llinás, R. et al. (1981) Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys. J. 33,
323–352
h Robinson, P.J. et al. (1994) Phosphorylation of dynamin I and synapticvesicle recycling. Trends Neurosci. 17, 348–353
i Südhof, T.C. (1995) The synaptic vesicle cycle: a cascade of protein–protein
interactions. Nature 375, 645–653
j Llinás, R.R. et al. (1972) Calcium transients in presynaptic terminal of
squid giant synapse: detection with aequorin. Science 176, 1127–1129
k Llinás, R.R. et al. (1994) Localization of calcium concentration microdomains at the active zone in the squid giant synapse. Adv. Sec. Mess.
Phosph. Res. 29, 133–138
l Llinás, R. et al. (1995) The concept of calcium concentration microdomains in synaptic transmission. Neuropharmacol. 34, 1443–1451
m Stanley, E.F. (1993) Single calcium channels and acetylcholine release
at a presynaptic nerve terminal. Neuron 11, 1007–1011
n Stanley, E.F. (1997) The calcium channel and the organization of the
presynaptic transmitter release face. Trends Neurosci. 20, 404–409
o Stanley, E.F. (1995) Calcium entry and the functional organization of
the presynaptic transmitter release site. In Excitatory Amino Acids and
Synaptic Transmission (Wheal, H.V. and Thomson, A.M., eds), pp. 17–27
Academic Press
p David, P. et al. (1993) Expression of synaptotagmin and syntaxin associated with N-type calcium channels in small cell lung cancer. FEBS
Lett. 326, 135–139
q El Far, O. et al. (1993) Synaptotagmin associates with presynaptic calcium channels and is a Lambert–Eaton myasthenic syndrome antigen.
Ann. New York Acad. Sci. 707, 382–385
r O’Connor, V. et al. (1993) On the structure of the synaptosecretosome:
evidence for a neurexin/synaptotagmin/syntaxin/Ca21 channel complex.
FEBS Lett. 326, 255–260
the Ca21 current close to a release site will have a major influence on whether or not release of a fusioncompetent vesicle occurs at that site. In the study of
Sabatini and Regehr18, prolonging the presynaptic AP
by blocking the delayed rectifier current(s) (IDR) that
normally curtail(s) the AP, increased the total Ca21
influx at the granule-cell to Purkinje-cell synapse in
cerebellum. The peak Ca21 current did not change (that
is, channel open probability is maximum during control APs) and the 23% increase in AP duration produced
only a parallel 25% increase in Ca21 influx. This, however, resulted in a twofold enhancement of the excitatory postsynaptic current (EPSC)18. Relatively small
proportional changes in the Ca21 influx can thus dramatically alter P when cooperative binding of up to
four Ca21 ions is required (Box 3).
Many of the proteins involved in synaptic release,
for example, synaptotagmin and munc 13, contain
phosphorylation sites. The combined effects of PKC
activation observed in in vitro biochemical studies predict an increase in the availability of vesicles for fusion
and a decrease in the Ca21 threshold for exocytosis19.
In the chick ciliary presynaptic terminal, activation of
PKC did increase P (and consequently reduced the
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expression of facilitation) without affecting the presynaptic AP, the associated Ca21 influx or steady-state
intracellular Ca21 concentration, [Ca21]i. In addition,
steady-state EPSC amplitude at high frequencies or recovery from frequency-dependent depression are unaltered (although elsewhere PKC might mobilize vesicles
attached to the cytoskeleton). A leftward shift in the
relationship between extracellular Ca21 concentration,
[Ca21]o, and release suggested that PKC also increased
the Ca21 affinity of the release machinery20. Thus, some
of the differences in low-frequency release probability
at different synapses might be due to a differential expression of proteins that provide molecular brakes on
the release machinery (Fig. 1) or differences in their
differential phosphorylation.
Presynaptic Ca21 channels can be positively or negatively modulated. For example syntaxin, a plasmamembrane protein that forms part of the fusion-core
complex, increases the sensitivity of N-type Ca21 channels to suppression by G-protein-coupled receptors21,
whereas CSPs in the vesicular membrane reduce this
interaction and promote interactions of these channels
with other proteins at the release site5. The balance
between such mechanisms might determine P.
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(a)
(b)
Docking
Molecular brakes
Unlocking
solic
Cyto tor
fac
Synaptobrevin
dissociates from
synaptophysin
Synaptophysin
Synaptobrevin
Transmitter
ptoSyna
in
brev
Synaptotagmin
C2
DO
Mint
Neurexin
Plasma Munc18
SNAP25
membrane
Syntaxin
Syntaxin
Low energy
complex
(c)
Syntaxin dissociates
from munc18
Ca2+
channel
(d)
ATP
NSF
ADP
Ca2+-dependent
fusion
Rabphilin−RIM
Rab-GTP
Rabphilin-RIM
NSF−αSNAP
Rabphilin−RIM
Rab-GTP
Rab-GDP
High-energy
monomers
Ca2+
CSP
Fusion core complex
retarded by CSP
Syntaxin suppresses Ca2+
channels in the absence
of CSP
Fusion core complex
with NSF−αSNAP bound
Neighbouring
vesicles are
retarded
Action
potential
opens
Ca2+
channels
Ca2+
trends in Neurosciences
Fig. 1. The basic components of the transmitter release machinery. This simplified scheme aims to capture the essential components. It is not
intended to be a complete description of the mechanisms involved. (a) Docking involves interactions between proteins (and phospholipids) in the
vesicular membrane and proteins in the plasma membrane at an active zone. The ‘molecular brakes’ restrict entry of the fusion-core proteins
(SNAREs or SNAP receptors) into the fusion-core complex. These brakes include synaptobrevin or vesicle-associated membrane protein (VAMP) in
the vesicular membrane, which binds to synaptophysin11, an interaction that is promoted by a cytosolic factor (in adults)12. Syntaxin in the plasma
membrane binds to munc 18 (or munc 13), which prevents its entry into the fusion-core complex. Without a docked vesicle (and its associated
cystein string proteins – CSPs), Ca21 channels in the plasma membrane are suppressed by an interaction with syntaxin. (b) As vesicles dock, SNARE
proteins are ‘unlocked’ by, for example, an interaction between munc 18 and mint, which combines with DOC2 in the vesicular membrane and
unlocks syntaxin, so that it can bind SNAP25 (for reviews see Refs 7,10). (c) The fusion-core complex forms (synaptobrevin, syntaxin and SNAP25)
and becomes a high-affinity binding site for aSNAP, which then binds the ATPase, NSF (Ref. 13). SNARE proteins exist in a high-energy state as
monomers, but release energy on complex formation (it is proposed that this energy could, for example, be used to force vesicular and plasma
membranes together). Regeneration of the monomers requires ATP to be hydrolysed and repeated cycles of core-complex formation have been proposed to ‘zip’ the two membranes together (for a review, see Ref. 4). The fusion-core complex can, however, be held in stasis, for example, by
CSPs in the vesicular membrane. (d) Fusion occurs when a fully release-competent vesicle receives an adequate influx of Ca21 through the voltage-gated channels that form an integral part of the release machinery and the contents of the vesicle are discharged into the synaptic cleft. After,
or during, Ca21-triggered fusion, RAB proteins in the vesicular membrane hydrolyse their bound GTP, and RAB–GDP and its bound effector protein
(rabphilin or RIM) dissociate from the vesicle. This action in some way retards activation of neighbouring vesicles4,14. Abbreviations: NSF, N-ethylmaleimide-sensitive factor; RIM, RAB3-interacting molecule; SNAP, soluble NSF attachment protein; SNARE, SNAP receptor; SNAP25, 25 kD synaptosomal-associated protein. Reproduced, with permission, from Ref. 15.
Release probability varies dramatically from
connection to connection
Release probability is rarely 1, even after significant
periods of rest, and can vary widely. Estimates vary from
,0.01 at specific pyramidal-cell to interneurone connections in the neocortex (see, for example, Ref. 22), to
as high as 0.9 at the calyx of Held (Ref. 23) and at pyramidal inputs onto other classes of interneurones in CA1
(Ref. 24), with pyramidal-cell to pyramidal-cell connections being intermediate (0.3–0.6, Refs 24,25). Thus, at
low frequencies, a release will either occur at every contributory release site in response to 90% of presynaptic
APs, or only once per site for >100 APs. Clearly, at synapses exhibiting a high probability, vesicle depletion
(and depression) will be rapid and profound (Box 2),
whereas at synapses exhibiting a low probability, depletion at low firing rates will be negligible. Although the
mechanism or mechanisms that underlie this 100-fold
difference, even at the terminals of a single presynaptic
axon, have yet to be identified, the type of target neurone clearly has a central role in its determination25–31.
Even when an axon innervates an inappropriate target,
that target (rather than the axon) determines whether
transmitter release is tonic or phasic32.
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Box 2. Release-site refractoriness
Release-site refractoriness accounts for the major presynaptic component of paired-pulse depression at central synapsesa–e (see also Refs f,g
and Ref. h for central inhibitory synapses). After exocytosis, it appears
that each release site is refractory for some tens of milliseconds and,
during this time, second EPSP amplitude is inversely related to the amplitude of the first EPSP. A simple explanation is that the immediately releasable pool of transmitter is partially depleted by the first AP,
leaving a smaller population of fusion-competent vesicles available for
the second. The immediately releasable pool would include those
vesicles that are docked, fully release-competent and not retarded.
One mechanism proposed for release-site refractoriness involves RAB3,
a small vesicular G protein. It is activated and liberated, with its associated effector proteins, only upon Ca21-dependent vesicle fusion. This
has been proposed to retard fusion of competent vesicles that are in
close proximity to the fused vesiclei,j. Such a mechanism would explain the physiological observations of release site refractoriness in
the face of morphological evidence for an excess of docked vesicles.
Frequency-dependent depression
Frequency-dependent depression has a much slower timecourse,
developing over minutes of repetitive firing and recovering slowly.
It involves depletion of the readily releasable pool of vesicles. These
would include the vesicles that are fusion-competent, the recently
docked vesicles that are not yet fusion-competent and the undocked
cytoplasmic vesicles that are in equilibrium with the recently docked
vesicles. This pool appears to comprise only a relatively small proportion of the total population of synaptic vescles at many central
synapses, the remainder, the reserve pool, is tethered to the cytoskeleton and unavailable for release. As recycling of discharged vesicles
takes tens of seconds, the readily releasable pool is depleted and release
depressed until a plateau at which the rate of release is matched by
the rate of replenishment is achieved. The rate of decline and the
final plateau amplitude are determined by the firing rate (for further
discussion of these and other factors contributing to presynaptic
depression see Ref. k).
References
a Thomson, A.M. and Bannister, A.P. (1999) Release-independent depression
at pyramidal inputs onto specific cell targets: dual recordings in slices
of rat cortex. J. Physiol. 519, 57–70
b Thomson, A.M. (1997) Activity-dependent properties of synaptic transmission at two classes of connections made by rat neocortical pyramidal
axons in vitro. J. Physiol. 502, 131–147
c Thomson, A.M. et al. (1993) Large, deep layer pyramid–pyramid single
axon EPSPs in slices of rat motor cortex display paired pulse and frequencydependent depression, mediated presynaptically and self-facilitation,
mediated postsynaptically. J. Neurophysiol. 70, 2354–2369
d Thomson, A.M. and Deuchars, J. (1994) Temporal and spatial properties
of local circuits in neocortex. Trends Neurosci. 17, 119–126
e Markram, H. (1997) Network of tufted layer 5 pyramidal neurons. Cereb.
Cortex 7, 523–533
f Markram, H. et al. (1998) Differential signaling via the same axon of
neocortical pyramidal neurons. Proc. Natl. Acad. Sci. U. S. A. 94, 719–723
g Markram, H. (1997) Network of tufted layer 5 pyramidal neurons. Cereb.
Cortex 7, 523–533
h Ouardouz, M. and Lacaille, J.C. (1997) Properties of unitary IPSCs in
hippocampal pyramidal cells originating from different types of interneurons in young rats. J. Neurophysiol. 77, 1939–1949
i Geppert, M. et al. (1997) The small GTP-binding protein rab3A regulates
a late step in synaptic vesicle fusion. Nature 387, 810–814
j Geppert, M. and Südhof, T.C. (1998) RAB3 and synaptotagmin: the yin
and yang of synaptic membrane fusion. Annu. Rev. Neurosci. 21, 75–95
k Thomson, A.M. Molecular frequency filters at central synapses. In
Progress in Neurobiology (in press)
Facilitation
Release correlates with both the steady-state [Ca21]i
and the size of the Ca21 transient33. If one or more of the
proposed four Ca21 binding sites associated with the release machinery is already occupied, a Ca21 transient that
is subthreshold when no sites are occupied, might now
reach release threshold (Fig. 2). Moreover, occupation
of one binding site increases the affinity at others and
Ca21 cooperativity declines with facilitation, which suggests prior occupation of some Ca21 binding sites34,35.
According to McLachlan1, the ‘residue of active Ca21 that
enters the terminal during its initial depolarization and
which still remains at the transmitter release sites when
the successive impulses arrive’ is proposed to underlie
facilitation (McLachlan1, after Refs 37–40). Facilitation
typically involves an increase in P, whereas several
forms of depression have been found to be associated
with a decrease in n (Refs 16,40).
Mallart and Martin measured the time constant for
decay (tdecay) of facilitation to be between 50 ms and
300 ms at the frog neuromuscular junction41. At the
‘low P’ facilitating inputs from pyramidal axons onto
certain classes of interneurones, facilitation decays rapidly (tdecay 30–40 ms, adult cortex, 35–368C). Sixty milliseconds after the first AP, facilitation is almost unmeasurable42. Like release-site refractoriness (Box 2),
facilitation decays more slowly at immature central
synapses25,31, but in each age group these two pairedpulse effects have a similar timecourse, with the more
dominant often obscuring the effects of the other. Facilitation can be observed only at non-refractory release
sites, mostly those at which the first AP has failed to
release transmitter. Whether a paired-pulse protocol
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results, on average, in depression or facilitation therefore depends on whether the majority of available
release sites are fully activated by the first AP and are
then refractory, or whether a large proportion of sites
bind some, but less than four Ca21 ions during the first
AP (priming the release site but not causing release).
Augmentation
Augmentation is also Ca21 dependent: presynaptic
injection of EGTA (a Ca21 chelator) prevents augmentation without affecting low-frequency release, or synaptic depression (squid giant synapse43). However, augmentation decays more slowly than facilitation (tdecay, 7 s at
the frog neuromuscular junction) and ‘each impulse
adds an increment of potentiation and increases tdecay of
potentiation’44. At strongly facilitating pyramidal cell to
interneurone connections in the neocortex, augmentation is readily apparent. Each successive EPSP in a brief
train is enhanced more than the preceding EPSP, even
when the interval between these later EPSPs is longer
than the decay time for paired-pulse facilitation. The
decay of fourth EPSP augmentation is slower than the
decay of third EPSP augmentation, and enhancement
of the fifth or sixth EPSP is measurable 3 s after a brief
train42 (Fig. 3). Once initiated therefore, augmentation
is maintained at frequencies below those that result in
release-site refractoriness. Augmentation is, however, dependent on significant facilitation developing first42.
Somehow, possibly by initiating a Ca21-dependent
priming step, facilitation appears to be important for
the development of augmentation.
This pattern of facilitation and augmentation
matches the patterns of firing that pyramidal cells generate from the start of a maintained excitatory input.
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(a)
(c)
Release
sites primed
by Ca2+
2nd EPSPs at
4 interspike
intervals
5 mV
Synaptophysin
60 ms
NSF−aSNAP
Glutamate
Synaptotagmin
(d)
3rd EPSPs at
4 interspike
intervals
Ca2+ channel
Ca2+
5 mV
Syntaxin
Synaptobrevin SNAP25
(b)
100 ms
Primed sites
respond more
readily
(e)
4th EPSPs at
2 interspike
intervals
5 mV
Ca2+
200 ms
trends in Neurosciences
Fig. 2. Facilitation. (a) Facilitation is apparent particularly at low probability connections when the first spike fails to release transmitter from most
of the contributory release sites (that is, release-site refractoriness is not activated). However, the second, third or fourth spike initiates release (b).
Ca21 entering during the first action potential primes the release machinery (probably by binding to synaptotagmin), but with the first spike, too
few Ca21 ions bind to initiate release. (c) Responses to spike pairs and (d) and (e) to trains of three or four spikes at different interspike intervals
illustrate that the recovery from the facilitation generated by a single preceding spike occurs within 60 ms. Recovery after two or three preceding
spikes takes longer, as augmentation also begins to develop. Reproduced, with permission, from Ref. 15.
A brief spike pair or spike burst is typically followed by
significant frequency adaptation and lower frequency
firing; a pattern that first primes and then maintains
augmentation. By contrast, at ‘high P’ synapses, this
firing pattern optimizes depression: with depletion
first of the immediately releaseable pool and then of
the readily releasable pool of transmitter (Box 2). It
will be of interest in the future to study in equivalent
detail the patterns of release at different terminals of
other axons, whose neurones generate firing patterns
with different instantaneous frequency distributions.
However, these parameters should be studied at physiological temperatures, as the Q10s for all components
of this complex machinery will not necessarily be
identical.
When and where are facilitation and
augmentation expressed functionally?
These facilitating or augmenting effects are not readily apparent if P is very high and most available release
sites have become refractory after the first AP. However,
if many events are recorded and those in which the postsynaptic event is unusually small are selected for analysis, facilitation of the second EPSP, even at very high P
connections can be demonstrated24. Pyramidal cell to
pyramidal cell connections are an intermediate example
that typically exhibit depression, but are able to express
facilitation after first-spike failures24 or if Ca21 influx is
reduced. What remains unclear is the degree to which
these connections can express augmentation, even when
P is reduced by reducing Ca21 influx. Transmission in response to all but the second spike in the train at all tested
frequencies is significantly reduced, and augmentation
is very much less developed than at ‘low P’ connections
under control conditions. If augmentation is dependent
on raised [Ca21]i, reducing Ca21 influx might prevent
its full expression (see below). In a few recent studies
(see, for example, Ref. 48, climbing-fibre to Purkinjecell synapse), Ca21 entry was lowered and P was reduced,
but no facilitation was revealed. Whether the mechanism underlying facilitation is absent at these synapses
or whether P was simply not reduced sufficiently for
facilitation to be revealed, remains unclear (events after
first-spike failures were not analysed).
The mechanisms underlying augmentation
With cooperative Ca21 binding (Box 3), unbinding
rates would change with occupation. Occupancy of a single site might decay within a few tens of milliseconds,
whereas binding at a third site might decay more slowly.
However, tdecay for augmentation continues to increase
with spike number well beyond three APs. The decay
of augmentation is proposed to represent removal of
intraterminal Ca21. It is slowed by Na1 accumulation
(which slows Ca21 extrusion by Na1–Ca21 exchange) or
by the binding of Ca21 to intracellular buffers49. Augmentation might therefore result from a slowing of the
decay of [Ca21]i as Na1 accumulation and intracellular
buffering of Ca21 increases with spike number.
In cerebellar granule-cell terminals, Ca21 accumulated
during stimulation. Thereafter, [Ca21]i decayed with three
exponentials, tdecay values of 100 ms (90%), 6 seconds
(9%) and 1–2 min. During stimulation, Na1 accumulation exhibited two components, one rapid and one
rising slowly over hundreds of milliseconds. After stimulation [Na1]i decayed with two exponentials (6–17 s and
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Potentiation
21
21
Box 3.The relationship between [Ca ]o or Ca
entry and release is S-shaped
The action of Ca21 at the release site is cooperative. More than one Ca21
ion must bind to the release machinery to trigger release. Second, third
and fourth power relationships between Ca21 entry and release have been
describeda–f. The consensus is now that three to four bound Ca21 ions per
Ca21 sensor are required (see Refs g,h for further discussion) and that a relatively high [Ca21]i is needed at the release site (estimates vary from a few
micromolar using high affinity Ca21 indicators, to several hundred micromolar using low affinity reporters, see Ref. i for discussion). This 3rd or 4th
power relationship is extremely important because small changes in the
Ca21 influx will have dramatic effects on the release probability.
References
a Katz, B. and di Mile, R. (1970) Further study of the role of calcium in synaptic
transmission. J. Physiol. 207, 789–801
b Hubbard, J.L. et al. (1968) On the mechanism by which calcium and magnesium affect the release of transmitter by nerve impulses. J. Physiol. 196, 75–86
c Landau, E.M. (1969) The interaction of presynaptic polarization with calcium
and magnesium in modifying spontaneous transmitter release from mammalian nerve terminals. J. Physiol. 203, 281–299
d Augustine, G.J. et al. (1985) Calcium entry and transmitter release at voltageclamped nerve terminals of the squid. J. Physiol. 367, 163–181
e Dodge, F.A. and Rahamimoff, R. (1967) Co-operative action of calcium ions in
transmitter release at the neuromuscular junction. J. Physiol. 193, 419–432
f Reid, C.A. et al. (1998) N- and P/Q-type Ca21 channels mediate transmitter release
with a similar cooperativity at rat hippocampal autapses. J. Neurosci. 18, 2849–2855
g Stanley, E.F. (1997) The calcium channel and the organization of the presynaptic transmitter release face. Trends Neurosci. 20, 404–409
h Stanley, E.F. (1995) Calcium entry and the functional organization of the
presynaptic transmitter release site. In Excitatory Amino Acids and Synaptic
Transmission (Wheal, H.V. and Thomson, A.M., eds), pp. 17–27, Academic
Press
i Kasai, H. and Takahashi, N. (1999) Multiple kinetic component and the Ca21
requirements of exocytosis. Philos. Trans. R. Soc. London Ser. B 354, 331–335
2–3 min). When [Na1]o was reduced, the rapid phase of
[Ca21]i decay was also reduced, indicating that Na1–Ca21
exchange accounts for the early component of Ca21 extrusion, whereas the Ca21-ATPase becomes more important as [Na1]i rises50. When spontaneous miniature
postsynaptic currents in hippocampal cultures were analysed, however, blocking Na1–Ca21 exchange produced
variable effects, unless Ca21 buffering by mitochondria
was also inhibited51. This difference could reflect
different relative contributions made by the [Ca21]iregulating mechanisms at different synapses (or at different stages of development), differential inclusion of
mitochondria near release sites (see, for example, Ref.
52) or the independent regulation of AP-triggered and
spontaneous AP-independent release. At the crayfish
neuromuscular junction, a large hyperpolarization follows tetanic stimulation and declines with a tdecay
similar to that of augmentation (10–20 s), suggesting
parallel changes in ion conductances or ion
accumulation, or both53. Facilitation is not, however,
accompanied by any increase in AP amplitude, which
declines at short interspike intervals.
Alternatively, or in addition, augmentation might
result where many release sites are occupied by incompletely fusion-competent vesicles or by competent
vesicles that are held in stasis by protein–protein interactions. The accelerated transition of these vesicles to
fusion competence by the many Ca21-dependent alterations in protein chemistry could also contribute to
augmentation. These changes would only contribute
to facilitation if they were extremely rapid, because at
cortical connections facilitation is maximal at 2–3 ms
(Ref. 42).
310
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Potentiation (post-tetanic potentiation or PTP) is
more slowly developing than facilitation or augmentation, and decays more slowly (tdecay tens of seconds
to minutes, see, for example, Refs 54,55). It is thought
to result from the Ca21-dependent mobilization of the
reserve pools of vesicles and requires relatively highfrequency or tetanic firing for sufficient Ca21 loading
of the terminals (Fig. 3). If mobilization of the reserve
pool is indeed the mechanism, it suggests that a larger
readily releasable pool (Box 2) can shift the equilibrium between undocked and docked vesicles, which
could increase occupancy of release sites (and maintain functional n). An increase in the amplitude of the
presynaptic AP has also been recorded between 1s and
7 s after trains of 50 stimuli at 200 Hz at the mammalian neuromuscular junction55 and could underlie
an increased P.
Potentiation and augmentation probably account for
the gradual increase (over a 15–20 minute period) in amplitude of the first EPSP of brief trains elicited at 1 Hz at
‘low P’, facilitating connections from pyramidal cells
to interneurones in neocortex22 (see also Refs 49,56). This
protocol changes the pattern of release more effectively than simply changing [Ca21]o (from 1 to 5 mM).
The decrease in paired-pulse facilitation as the amplitude
of the first EPSP increases and the decrease in first-spike
failures indicate an increase in P. In 5 mM [Ca21]o, this repetitive burst protocol eventually results in pairedpulse and brief-train depression. In vitro synaptic events
elicited by single APs, or brief trains at low repetition
rates are usually studied to obtain the stability required
for pharmacological or for statistical analysis. However,
although neurones might at times be quiescent for seconds or even minutes in vivo, they can also be active
for long periods and could alternate between release
modes as augmentation and potentiation on the one
hand and depletion on the other.
A simple circuit with a role in pattern generation?
An example of alternating patterns of presynaptic
firing in vivo is seen in the hippocampus during exploration, particularly of a novel environment. Periods of
theta activity appear as oscillations in the EEG at a frequency of 5–12 Hz, which cease when exploration ceases.
Pyramidal cells fire on the negative phase of the wave:
some generate burst discharges, some produce single
spikes and some do not contribute to the rhythm generated under those particular behavioural conditions.
The timing also varies: some cells fire earlier in each cycle
than others. Consolidation of the stronger synaptic inputs that cause the earliest firing in each cycle is proposed to underlie acquisition of a memory for that behaviourally relevant cue, such as the position of the
animal in the environment. As the period of theta
activity progresses, there is a shift in phase; cells that
were already active early in each cycle fire even earlier,
whereas those that fired later are further delayed or
silenced57–59. There is significant subcortical control of
the hippocampus and neocortex, and the circuitry described below should be seen only as a simple framework upon which other inputs impinge.
The connections made by CA1 pyramidal axons with
other pyramids are moderately ‘high P’ and depress
upon repetitive activation60. They will be maximally
effective early in each period of theta activity, but
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A.M. Thomson – Facilitation, augmentation and potentiation at central synapses
will depress strongly both during and across cycles. In
addition, only those Schaffer collateral inputs that
arrive early in each cycle will have the opportunity to
consolidate before inhibition is recruited.
Many basket and bistratified cells (inhibiting somata
and intermediate dendrites of pyramidal cells, respectively) receive ‘high P’ depressing inputs from pyramidal cells61. These cells will be readily recruited by CA1
pyramidal firing early in each theta period and cycle, and
will then suppress pyramidal firing and shunt Schaffer
collateral inputs, respectively. This inhibitory control
will not only regulate which cells fire or which inputs
are shunted, but, equally importantly, impose a temporal window during which afferent inputs can be most
effective and have the opportunity to consolidate.
Oriens-lacunosum moleculare (OLM) interneurones
inhibit the very distal apical dendritic tufts of pyramidal cells (where monosynaptic entorhinal cortex input
to CA1 arrives). OLM cells receive almost all their excitatory input from local pyramidal cells62 via ‘low P’
synapses that facilitate and augment during repetitive
activity63. These synapses will be almost totally ineffective at the start of theta activity. Even synchronous
firing of many presynaptic neurones will not enhance postsynaptic excitation if most of the coincident
spikes fail to elicit any transmitter release at all. However, when their presynaptic pyramidal partners fire in
bursts, these synapses facilitate, recruiting the OLM
interneurones. Early in the theta period, OLM cells will
be recruited only towards the end of the pyramidal-cell
bursts. However, as the period of theta activity progresses, augmentation will enhance earlier EPSPs until
single presynaptic spikes elicit significant postsynaptic
responses. The recruitment of these interneurones and
shunting of the entorhinal inputs will thus shift to an
earlier phase of the cycle as the theta period proceeds.
Inputs that are too weak or too late to contribute significantly to early pyramidal firing will be suppressed.
The type of consolidation that results from coincidence of EPSPs with back propagating APs (Ref. 64), or
dendritic Ca21 spikes involves an increase in ‘P’ and a
shift to a more-phasic release pattern. The outcome is
again a strengthening only of the earliest phase of excitation. Theta activity would thus lead to consolidation of
those synapses (from entorhinal cortex and from CA3)
that consistently contribute to the earliest pyramidalcell APs in each cycle. Inputs that contribute randomly or weakly, with less contextual relevance,
would be suppressed. The difference in the frequency
filtering properties of pyramidal inputs onto bistratified and onto OLM interneurones will result in different ‘windows of opportunity’ for consolidation of
Schaffer collateral versus entorhinal inputs. Early in
an exploratory phase, shunting inhibition will affect
Schaffer termination fields before it reaches entorhinal cortex inputs. The longer theta activity lasts, however, the more potent and selective the filtering produced by the OLM cells will be.
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(a)
Reserve
pool
Potentiation:
mobilization of the
reserve pool
Ca2+
?
Synapsin tethers
vesicles to the
cytoskeleton
Intracellular stores
slow [Ca2+]i decay
CaMK
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Readily releasable
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Postsynaptic
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1−5 bursts
per s
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1−5 bursts
per s
1 burst
per 5 s
Augmentation
Potentiation
Recovery
5 mV
50 ms
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Acknowledgements
The work from the
author’s laboratory
referred to in this
article was
supported by the
Medical Research
Council and
Novartis Pharma
(Basel). The author
thanks R. Llinás,
E. Stanley and
T. Sihra for their
advice in the
preparation of this
article.
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Coming soon in TINS
Neuroscience, no less than other scientific fields, is a subject of
controversy. The amount of information provided seems to
expand exponentially, creating confusion and uncertainty.
Particularly susceptible to these are research areas that now
bridge more than one traditional level or topic of expertise.
Researchers in different disciplines find that they have to be able
to interpret and understand the key issues from other disciplines.
Much like guests at weddings, the two sides can be suspicious of
each other until they get to know one another better. In coming
months, TINS will be publishing a series of provocative essays,
‘Soundings’, designed to highlight differences or controversies in
topical or nascent fields. The articles are intended to stimulate
debate and reaction, which we welcome in the correspondence
pages of the journal. Be prepared!