J Neurophysiol 98: 1862–1870, 2007.
First published July 18, 2007; doi:10.1152/jn.00510.2007.
Muscarinic Receptor–Dependent Long-Term Depression in Rat Visual Cortex
Is PKC Independent but Requires ERK1/2 Activation and Protein Synthesis
Portia A. McCoy1 and Lori L. McMahon1,2
1
Departments of Neurobiology and 2Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama
Submitted 7 May 2007; accepted in final form 12 July 2007
INTRODUCTION
Cholinergic innervation of visual cortex is essential for
normal processing of visual stimuli required for vision dependent learning, such as face recognition and certain spatial
memory tasks (Bentley et al. 2004; Mayo et al. 1988; Sato et
al. 1987a,b). Acetylcholine (ACh) released in visual cortex in
response to visual stimuli, as well as exogenous application of
ACh, causes an increase in cellular activity for optimal stimulus orientation (Fournier et al. 2004; Himmelheber et al. 2000;
Laplante et al. 2005); this cholinergic dependent neuronal
activation occurs through muscarinic acetylcholine receptors
(mAChRs) (Sato et al. 1987b). In visual cortex, mAChR
activation is also responsible for synchronizing neuronal activity, which has been implicated in associative and perceptual
learning (Gruber et al. 2001, 2002; Miltner et al. 1999) and in
short-term memory (Rodriguez et al. 2004; Tallon-Baudry et
al. 1998). Furthermore, mAChRs mediate rapid changes in
visual cortical excitability in human visual cortex induced by
Address for reprint requests and other correspondence: L. L. McMahon,
Dept. of Physiology and Biophysics, UAB, 1918 University Blvd., MCLM
964, Birmingham, AL 35294-0005 (E-mail: [email protected]).
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periods of light deprivation (Boroojerdi et al. 2001), which
may be explained by the ability of mAChRs to reduce K⫹
channel currents, thereby directly controlling neuronal excitability (McCormick et al. 1993).
To further support a role for ACh in visual system processing, depletion of this neurotransmitter by lesioning nucleus
basalis magnocellularis (NbM), the origin of cholinergic innervation to visual cortex (Wenk et al. 1980), causes decreased
responses and selectivity to all visual stimuli (Sato et al. 1987a)
and impairs visually oriented learning and memory in animal
models (Hepler et al. 1985; Mayo et al. 1988). Moreover, in
humans, blocking mAChRs impairs performance in visual
memory tasks, such as face recognition (Drachman and Leavitt
1974; Thiel et al. 2002). Such effects mimick some of the
deficits in Alzheimer’s patients, in whom loss of the NbM cell
population results in both visual disturbances and spatial memory deficits (Bodick et al. 1997; Dunnett and Fibiger 1993;
Perry et al. 1999; Whitehouse et al. 1982). Thus it is clear that
the cholinergic innervation in visual cortex is critical for
normal cognitive processing.
Long-term modulation of synaptic efficacy is believed to be
a cellular substrate of learning and memory (Malenka and Bear
2004; Whitlock et al. 2006). Long-term changes in synaptic
strength mediated by cholinergic receptor activation may explain the cholinergic dependence of normal learning and memory in visual cortex. Activation of G␣q-coupled m1 receptors
induces an activity dependent and partially N-methyl-D-aspartate (NMDA) receptor (NMDAR)-dependent long-term depression (LTD) at layer 2/3 synapses in acute rat visual cortex
slices (Kirkwood et al. 1999). However, the signaling cascade
downstream of m1 receptor activation required for LTD induction has not been defined. The goal of this study is to identify
the signaling molecules involved and the role of protein synthesis in the induction, expression, and maintenance of this
plasticity.
METHODS
Experiments were conducted with an approved protocol from the
University of Alabama at Birmingham Institutional Animal Care and
Use Committee, in compliance with National Institutes of Health
guidelines.
Electrophysiology
All experiments were performed using standard methods (Scheiderer et al. 2006). Three- to 4-wk-old Sprague-Dawley rats were
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0022-3077/07 $8.00 Copyright © 2007 The American Physiological Society
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McCoy PA, McMahon LL. Muscarinic receptor– dependent longterm depression in rat visual cortex is PKC independent but requires
ERK1/2 activation and protein synthesis. J Neurophysiol 98: 1862–1870,
2007. First published July 18, 2007; doi:10.1152/jn.00510.2007. Intact
cholinergic innervation of visual cortex is critical for normal processing of visual information and for spatial memory acquisition and
retention. However, a complete description of the mechanisms by
which the cholinergic system modifies synaptic function in visual
cortex is lacking. Previously it was shown that activation of the m1
subtype of muscarinic receptor induces an activity-dependent and
partially N-methyl-D-aspartate receptor (NMDAR)-dependent longterm depression (LTD) at layer 4 –layer 2/3 synapses in rat visual
cortex slices in vitro. The cellular mechanisms downstream of the
G␣q coupled m1 receptor required for induction of this LTD (which
we term mLTD) are currently unknown. Here, we confirm a role for
m1 receptors in mLTD induction and use a series of pharmacological
tools to study the signaling molecules downstream of m1 receptor
activation in mLTD induction. We found that mLTD is prevented by
inhibitors of L-type Ca2⫹ channels, the Src kinase family, and the
mitogen-activated kinase/extracellular kinase. mLTD is also partially
dependent on phospholipase C but is unaffected by blocking protein
kinase C. mLTD expression can be long-lasting (⬎2 h) and its
long-term maintenance requires translation. Thus we report the signaling mechanisms underlying induction of an m1 receptor-dependent
LTD in visual cortex and the requirement of protein synthesis for
long-term expression. This plasticity could be a mechanism by which
the cholinergic system modifies glutamatergic synapse function to
permit normal visual system processing required for cognition.
VISUAL CORTEX mLTD REQUIRES ERK AND TRANSLATION
The magnitude of the LTD induced was measured either at 35 or 115
min after agonist removal.
Chemicals
All drugs were made as 1,000 fold stock solutions in water or
DMSO and diluted immediately before use. All drugs were obtained
from Sigma (St. Louis, MO), except CCh, U0126, actinomycin D, and
U73122, which were acquired from Calbiochem (La Jolla, CA);
rapamycin, which was acquired from Cell Signaling Technology
(Danvers, MA); MTx-7, which was acquired from Peptides International (Louisville, KY); and PP2, which was acquired from Tocris
(Ellisville, MO).
RESULTS
Activation of muscarinic m1 receptors induces LTD at layer
2/3 synapses in rat visual cortex
In this study, we used extracellular fPSP recordings in layer
2/3 generated by layer 4 stimulation in acute visual cortex
slices to investigate the cellular mechanisms underlying CChinduced LTD (Kirkwood et al. 1999). LTD was induced using
a 10-min bath application of 50 ␮M CCh, a protocol adopted
from Kirkwood et al. (1999). This protocol elicits a transient
depression of the fPSP during drug application (64 ⫾ 5% of
baseline), followed by a long-lasting depression after agonist
washout that lasted for the duration of the experiment (Fig. 1,
A and B; 77 ⫾ 3% of baseline fPSP amplitude, n ⫽ 8, P ⬍
0.05). To determine if the transient depression and the longlasting depression are of pre- or postsynaptic origin, the paired
pulse ratio (PPR) was analyzed. A change in PPR is usually an
FIG. 1. Muscarinic long-term depression (mLTD) requires activation of m1 receptors. A: representative example and (B) summary
data showing that application of the cholinergic agonist carbachol
(CCh, 50 ␮M, 10 min) elicits an acute depression during agonist
application followed by a long-term depression after agonist washout that lasts the duration of the recording (n ⫽ 8). C: CCh
application causes a transient change in the paired pulse ratio (PPR)
that returns to baseline during mLTD expression (n ⫽ 8). D:
application of 50 ␮M CCh for 3 min is sufficient to induce LTD
(n ⫽ 6). E: CCh-induced LTD is prevented by 1 ␮M atropine, a
nonselective mAChR antagonist (n ⫽ 4). F: mLTD is inhibited by
75 nM pirenzepine (Pirenz), an m1 receptor antagonist (n ⫽ 5). G:
mLTD is prevented by 100 nM MTx-7 toxin, an m1 receptor
antagonist [control (Ctl), n ⫽ 7; MTx-7, n ⫽ 9]. H: bar chart shows
summarized data. Asterisk indicates statistical significance, P ⬍
0.05. Waveforms are averages of 20 events taken from 5 min before
and 35 min after agonist application. Scale bar, 0.5 mV, 10 ms.
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anesthetized by inhalation with isoflurane and decapitated. Coronal
slices (400 ␮m) from visual cortex were cut using a vibratome in high
sucrose artificial cerebrospinal fluid (ACSF; in mM): 85 NaCl, 2.5
KCl, 4 MgSO4, 0.5 CaCl2, 1.25 NaH2PO4, 25 NaHCO3, 25 glucose,
75 sucrose, 2 kynurenic acid, and 0.5 ascorbate. After a 30-min
incubation in the high sucrose aCSF, slices were stored in standard
ACSF (in mM): 119 NaCl, 2.5 KCl, 2.5 CaCl2, 1.3 MgSO4, 1
NaH2PO4, 26 NaHCO3, and 10 glucose (pH 7.4), containing 2 mM
kynurenic acid. Slices were transferred to a submersion recording
chamber and perfused with oxygenated ACSF without kynurenic acid
at 27–30°C at a rate of 3– 4 ml/min. Extracellular field potentials in
layer 2/3 were recorded with an Axopatch 200B amplifier (Molecular
Devices). A stainless steel bipolar stimulating electrode (FHC, Bowdoinham, ME) was placed in layer 4, and a glass microelectrode filled
with 2 M NaCl was placed in layer 2/3 to record extracellular field
potentials. The stimulus duration was set at 0.1 ms, and the stimulus
intensity was adjusted to yield a baseline field postsynaptic potential
(fPSP) of 0.3– 0.6 mV. Synaptic events were collected at 0.1 Hz. The
peak amplitude of the synaptic response was measured and plotted
versus time, each point representing the average of five consecutive
data points. Data were acquired and stored using custom software
written in Labview (gift from Richard Mooney, Duke University).
Data are presented as mean ⫾ SE. Statistical significance was determined using Student’s unpaired or paired t-test where appropriate, and
results were considered significant at P ⬍ 0.05. Only experiments
with ⬍5% change in the original baseline were included in the
analysis.
After acquisition of a stable baseline of transmission (ⱖ20 min),
mLTD was induced using a 10-min bath application of 50 ␮M
carbachol (CCh), consistent with procedures previously published
(Kirkwood et al. 1999; Scheiderer et al. 2006), unless stated otherwise. Antagonists were bath applied ⱖ10 min before CCh application.
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amplitude in interleaved controls, n ⫽ 7, P ⬍ 0.05). Together,
these data indicate that mLTD induction requires activation of
the m1 subtype of mAChRs.
mLTD induction does not require a change in inhibition or
activation of NMDARs but does require presynaptic activity
and activation of L-type Ca2⫹ channels
Because the fPSP is a result of activation of both inhibitory
and excitatory synapses, we next determined whether mLTD is
a consequence of depression of excitatory transmission rather
than an increase in inhibitory transmission. To study a potential
role of synaptic inhibition in mLTD, we bath applied the
GABAA antagonist picrotoxin (100 ␮M) and attempted to
induce mLTD. The mLTD magnitude was not different in
picrotoxin compared to control, indicating that the depression
of the fPSP is not a result of increased inhibitory transmission
(Fig. 2A; 75 ⫾ 5% of baseline fPSP amplitude n ⫽ 6, vs. 77 ⫾
3% of baseline amplitude in control slices n ⫽ 8; P ⬎ 0.05).
To confirm that mLTD requires presynaptic activity as
shown previously (Kirkwood et al. 1999), stimulation was
halted during CCh application and resumed 3 min after to
allow sufficient washout of the agonist from the recording
chamber. Using this protocol, mLTD induction was prevented
(Fig. 2B; 100 ⫾ 2% of baseline fPSP amplitude, n ⫽ 5, vs.
78 ⫾ 1% of baseline amplitude in interleaved control slices,
n ⫽ 6, P ⬍ 0.05), indicating that presynaptic activity is
required. Although mLTD induction was previously reported
to be partially dependent on NMDAR activation (Kirkwood et
al. 1999), we found that mLTD induction is completely unaffected by the NMDAR antagonist D,L-2-amino-5-phosphopentanoic acid (APV; Fig. 2C; 78 ⫾ 4% of baseline fPSP amplitude in 100 ␮M APV, n ⫽ 9, vs. 74 ⫾ 6% of baseline fPSP
amplitude in interleaved control slices, n ⫽ 6, P ⬎ 0.05).
Because most forms of long-term synaptic plasticity at glutamate synapses, including electrically induced LTD at synapses
in visual cortex, require a rise in postsynaptic Ca2⫹ for induc-
FIG. 2. mLTD induction is not caused by a change in inhibition,
is activity-dependent, and is N-methyl-D-aspartate receptor (NMDAR)independent, but requires activation of L-type channels. A: mLTD
induction is unaffected by GABAA antagonist picrotoxin (100 ␮M,
Picro, n ⫽ 6). B: interruption of stimulation (No Stim) during
application of CCh prevents induction of mLTD (n ⫽ 5). C: mLTD
induction is unaffected by NMDAR antagonist D,L-APV (100 ␮M,
n ⫽ 9). D: mLTD induction is prevented by nifedipine, an L-type
Ca2⫹ channel inhibitor (10 ␮M, n ⫽ 6). E: bar chart shows summarized data. Asterisk indicates statistical significance, P ⬍ 0.05.
Waveforms are averages of 20 events taken from 5 min before and 35
min after agonist application. Scale bar in A, 0.25 mV, 10 ms; in B–D,
0.5 mV, 10 ms.
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indicator of a presynaptic locus of expression, whereas no
change is an indicator of a postsynaptic locus (Dobrunz and
Stevens 1997). Analysis shows a change in PPR during CCh
application, indicating a transient presynaptic depression of
glutamate release consistent with previous reports (Kimura and
Baughman 1997; Mrzljak et al. 1993), but not during expression of the long-lasting depression (Fig. 1C; 107 ⫾ 4% of
baseline PPR, n ⫽ 8, P ⬎ 0.05), suggesting that a postsynaptic
expression mechanism underlies the LTD. To determine the
threshold duration of CCh application needed to induce LTD,
we applied CCh for different lengths of time. The threshold lies
between 2 and 3 min, because a 2-min application of CCh is
insufficient to induce LTD (data not shown), whereas a 3-min
application induces LTD (Fig. 1D; 80 ⫾ 1% of baseline fPSP
amplitude, n ⫽ 6, P ⬍ 0.05). However, to study signaling
mechanisms underlying this LTD, we used the 10-min application of CCh. To confirm that the CCh-induced LTD measured at synapses in layer 2/3 requires activation of muscarinic
acetylcholine receptors (mAChRs) rather than nicotinic acetylcholine receptors (nAChRs), the nonselective mAChR antagonist atropine was applied at 1 ␮M, a concentration that blocks
all mAChR subtypes. Both the transient depression during CCh
application and the subsequent LTD were completely prevented (Fig. 1E; 97 ⫾ 2% of baseline fPSP amplitude in
atropine, n ⫽ 4, P ⬍ 0.05 compared to without atropine). Our
laboratory has characterized a similar LTD in hippocampus
that is dependent on mAChRs and has termed the plasticity
muscarinic LTD (mLTD) (Scheiderer et al. 2006). Activation
of the m1 receptor subtype is required for induction of mLTD
because it is prevented by the antagonist pirenzepine at a
concentration selective for m1 receptors (75 nM) (Marino et al.
1998) (Fig. 1F; 98 ⫾ 6% of baseline fPSP amplitude in
pirenzepine, n ⫽ 5, P ⬍ 0.05 compared to without pirenzepine), and it can be significantly decreased by preincubation
(⬎1 h) with the highly selective and irreversible m1 receptor
antagonist MTx-7 toxin (Fig. 1G; 88 ⫾ 3% of fPSP baseline in
100 nM MTx-7 toxin, n ⫽ 9, vs. 74 ⫾ 3% baseline fPSP
VISUAL CORTEX mLTD REQUIRES ERK AND TRANSLATION
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result from a change in inhibition, is activity dependent, is
NMDAR independent, and requires activation of L-type Ca2⫹
channels.
mLTD induction is partially dependent on phospholipase C
activation but is independent of PKC
tion (Brocher et al. 1992; Ismailov et al. 2004), we next tested
whether activation of L-type Ca2⫹ channels is required. Consequently, we found that blocking L-type channels with 10 ␮M
nifedipine prevented mLTD induction (Fig. 2D; 102 ⫾ 2% of
baseline fPSP amplitude in nifedipine, n ⫽ 6, vs. 79 ⫾ 2% of
baseline fPSP amplitude in interleaved control slices, n ⫽ 6,
P ⬍ 0.05). Together, these data showed that mLTD does not
FIG. 4. Induction of mLTD requires activation of Src kinases and extracellular signal-regulated kinases 1/2 (ERK1/2).
A: mLTD induction is blocked in the presence of the Src kinase
inhibitor, PP2 (10 ␮M) in interleaved control experiments
[control (Ctl), n ⫽ 6; PP2, n ⫽ 7]. B: mLTD induction is
prevented by the mitogen activated kinase/extracellular kinase
(MEK) inhibitor U0126 (20 ␮M), in interleaved control experiments (control, n ⫽ 5; U0126, n ⫽ 7). C: mLTD is unaffected
by the mtor inhibitor rapamycin (20 nM) in interleaved control
experiments [control, n ⫽ 4; rapamycin (rap), n ⫽ 5]. D: bar
chart shows summarized data. Asterisk indicates statistical
significance, P ⬍ 0.05. Waveforms are averages of 20 events
taken from 5 min before and 35 min after agonist application.
Scale bar, 0.5 mV, 10 ms.
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FIG. 3. mLTD induction requires partial activation of phospholipase C
(PLC) but does not require PKC activation. A: mLTD induction is partially
blocked by the PLC inhibitor U73122 (10 ␮M) in interleaved control experiments [control (Ctl) n ⫽ 7, U73122 n ⫽ 10]. B: mLTD induction is unaffected
by the PKC inhibitor chelerythrine (10 ␮M) in interleaved control experiments
(control, n ⫽ 6; chelerythrine, n ⫽ 8). C: bar chart shows summarized data.
Asterisk indicates statistical significance, P ⬍ 0.05. Waveforms are averages
of 20 events taken from 5 min before and 35 min after agonist application.
Scale bar, 0.5 mV, 10 ms.
m1 receptors couple to the G protein Gq, which stimulates
phospholipase C (PLC), resulting in cleavage of phosphatidylinositol (4,5)-bisphosphate (PIP2) into diacylglycerol (DAG)
and inositol 1,4,5-triphosphate (IP3), leading to activation of
protein kinase C (PKC) or release of Ca2⫹ from intracellular
stores, respectively. Application of 10 ␮M U73122, a PLCspecific antagonist, modestly but significantly inhibited mLTD
induction (Fig. 3A; 85 ⫾ 2% of baseline fPSP amplitude in
U73122, n ⫽ 10, P ⬍ 0.05, vs. 71 ⫾ 3% of baseline fPSP
amplitude in interleaved control slices, n ⫽ 7, P ⬍ 0.05),
whereas application of chelerythrine, an inhibitor of PKC
activity, was without effect (Fig. 3B; 70 ⫾ 7% of baseline fPSP
amplitude in 10 ␮M chelerythrine, n ⫽ 8, vs. 77 ⫾ 3% of
baseline fPSP amplitude in interleaved control slices, n ⫽ 6,
P ⬎ 0.05). These data indicate that mLTD induction is partially
dependent on PLC activation but is independent of PKC
activation.
Another signaling cascade downstream of m1-Gq coupling
is activation of the Src family of tyrosine kinases (Chan et al.
2005), which leads to the phosphorylation and activation of
mitogen activated kinase/extracellular kinase (MEK), followed
by phosphorylation and activation of extracellular signal-regulated kinases 1/2 (ERK1/2) (Rosenblum et al. 2000). To
determine if mLTD induction requires Src kinases, we examined the effects of an inhibitor of the Src family of kinases, PP2
(10 ␮M). We found that PP2 completely blocked mLTD (Fig.
4A; 107 ⫾ 5% of baseline fPSP amplitude in PP2, n ⫽ 7, vs.
74 ⫾ 5% of baseline fPSP amplitude in interleaved control
slices, n ⫽ 6, P ⬍ 0.05). We next studied whether ERK1/2
activation is required for mLTD induction using U0126 (20
␮M), a MEK inhibitor, and found that mLTD was completely
prevented (Fig. 4B; 97 ⫾ 3% of baseline fPSP amplitude in 20
␮M U0126, n ⫽ 7, vs. 78 ⫾ 4% of baseline fPSP amplitude in
interleaved control slices, n ⫽ 5, P ⬍ 0.05). [The time-course
of the CCh-induced transient depression in both PP2 and
U0126 appears truncated (also observed in nifedipine (Fig.
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P. A. McCOY AND L. L. McMAHON
Long-term maintenance of mLTD requires synthesis of new
proteins
Several forms of long-term plasticity, including LTD, have
been shown to require translation for either their induction
(Huber et al. 2000) or expression (Linden 1996; Sajikumar and
Frey 2003), and a requirement for protein synthesis has been
indicated in long-term memory formation (Davis and Squire
1984; Kelleher et al. 2004). Therefore we next studied whether
protein synthesis is required for mLTD induction and expression (up to 1 h) and/or for the long-term maintenance of mLTD
expression (L-mLTD, lasting ⬎1 h). To inhibit protein synthesis, anisomycin (25 ␮M) was bath applied; in control experiments, this inhibitor had no effect on basal transmission (data
not shown). Although there was no effect of protein synthesis
inhibition on mLTD expression during the first hour after
induction (Fig. 5A; 79 ⫾ 4% of baseline fPSP amplitude in
anisomycin, n ⫽ 8, vs. 78 ⫾ 3% of baseline fPSP amplitude in
interleaved control slices, n ⫽ 6, P ⬎ 0.05), the long-term
maintenance of expression (⬎1 h; L-mLTD) is prevented when
translation is inhibited with anisomycin from 20 min before to
35 min after agonist application (Fig. 5B; 100 ⫾ 4% of
baseline fPSP amplitude in anisomycin, T ⫽ 145, n ⫽ 5, vs.
74 ⫾ 5% of baseline fPSP amplitude in interleaved control
slices, n ⫽ 8, P ⬍ 0.05). Our finding that protein synthesis is
required for the long-term maintenance of mLTD led us to
question whether new RNA synthesis also plays a role in the
maintenance phase. To determine if this is the case, we preincubated slices in actinomycin D (25 ␮M) for 30 – 60 min
before recording (Huber et al. 2000). Blocking transcription
had no effect on either the induction, expression, or the
long-term maintenance of mLTD (Fig. 5C; 79 ⫾ 3% of
baseline fPSP amplitude in actinomycin D, T ⫽ 145, n ⫽ 6, vs.
76 ⫾ 3% of baseline fPSP amplitude in interleaved control
slices, n ⫽ 4, P ⬎ 0.05).
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FIG. 5. Long-term maintenance, but not induction of mLTD, requires new
protein synthesis. A: induction of mLTD (ⱕ40 min) is not altered in the
presence of 25 ␮M anisomycin (Ansio), an inhibitor of translation [control
(Ctl), n ⫽ 6; Aniso, n ⫽ 8]. B: at times past 1 h, long-term maintenance of
mLTD (L-mLTD) is blocked in the presence of anisomycin (control, n ⫽ 8;
Aniso, n ⫽ 5). C: mLTD and L-mlTD is unaffected in the presence of 25 ␮M
actinomycin D (Act D), a transcription inhibitor (control, n ⫽ 4; Act D, n ⫽
6). D: bar chart shows summarized data. Asterisk indicates statistical significance, P ⬍ 0.05. Waveforms are averages of 20 events taken from (A) 5 min
before and 35 min after or (B) 5 min before and 115 min after agonist
application. Scale bar, 0.5 mV, 10 ms.
DISCUSSION
Previously, Kirkwood et al. (1999) reported that activation
of m1 receptors induces LTD at synapses in layer 2/3 in acute
slices of visual cortex. Here we extend these findings by
showing that induction of mLTD requires activation voltagegated L-type Ca2⫹ channels, the Src family of tyrosine kinases,
ERK1/2, and is partially dependent on PLC. In addition, we
show that mLTD can be long-lasting and that its maintenance
requires new protein synthesis.
ml receptor– dependent LTD requires activation of ERK1/2
m1 receptors couple to the G protein G␣q and can increase
ERK1/2 activation after stimulation of either the PLC pathway,
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2D); however, the amplitude of the depression in either drug is
not different from CCh alone (74 ⫾ 5% in PP2, n ⫽ 7, vs. 59 ⫾
6% in control slices, n ⫽ 6, P ⬎ 0.05 and 75 ⫾ 5% in U0126,
n ⫽ 7, vs. 71 ⫾ 2% in control slices, n ⫽ 5, P ⬎ 0.05)].
Analysis of the PPR during CCh ⫾ PP2 or ⫾ U0126 is not
different from CCh alone (data not shown; 113 ⫾ 4% in PP2,
n ⫽ 7, vs. 120 ⫾ 8% in control slices, n ⫽ 6, P ⬎ 0.05 and
121 ⫾ 4% in U0126, n ⫽ 7, vs. 119 ⫾ 7% in control slices,
n ⫽ 5, P ⬎ 0.05), suggesting that any change in time-course is
most likely not a result of a presynaptic effect of PP2 or U0216
but rather a block of mLTD induction.
Because both Src and ERK1/2 have been shown to activate
mammalian target of rapamycin (mTOR) (Karni et al. 2005;
Tsokas et al. 2007), which is required for certain forms of both
long-term potentiation (LTP) and LTD (Banko et al. 2006;
Tsokas et al. 2007), we wanted to determine if mTOR played
a role in mLTD induction. Bath application of rapamycin (20
nM), an inhibitor of mTOR, had no affect on the mLTD
amplitude, indicating that mTOR activation is not required
(Fig. 4C; 85 ⫾ 4% of baseline fPSP amplitude in rapamycin,
n ⫽ 5, vs. 84 ⫾ 3% of baseline fPSP amplitude in interleaved
control slices, n ⫽ 4, P ⬎ 0.05). Together our findings show
that PLC (in part), the Src family of kinases, and ERK1/2 are
required for mLTD induction at synapses in layer 2/3 of visual
cortex.
VISUAL CORTEX mLTD REQUIRES ERK AND TRANSLATION
Calcium influx is required for mLTD induction
Our findings that mLTD is prevented by blockade of L-type
voltage-gated Ca2⫹ channels (rather than by NMDARs) suggests that a rise in postsynaptic Ca2⫹ is required for induction.
How a role for L-type channels interfaces with signaling
stimulated by m1 receptors is unknown and remains to be
studied. We anticipate that the L-type channels required for
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mLTD induction are activated after AMPAR-mediated depolarization of the postsynaptic cell, perhaps together with a
direct m1 receptor mediated postsynaptic depolarization. Previously, in visual cortex, it has been shown that activation of
mAChRs on layer 2/3 pyramidal cells causes a reduction in
both a slow Ca2⫹-activated K⫹ current and a voltage-dependent K⫹ current, resulting in a depolarization of the postsynaptic cell (McCormick et al. 1993), although the mAChR
subtype responsible was not identified. In other areas of the
CNS, such as hippocampus and entorhinal cortex, m1 receptor
activity specifically has been shown to depolarize the postsynaptic cell and modulate channel activity, controlling neuronal
excitability (Klink and Alonso 1997; Muller et al. 1988).
Protein synthesis and memory
Synthesis of new proteins is required for long-term memory
in humans and in experimental animal models (Davis and
Squire 1984; Idzikowski and Oswald 1983; Kelleher et al.
2004). This requirement has been shown for both induction and
expression of various forms of LTD, both in vitro and in vivo,
including those requiring NMDARs (Manahan-Vaughan et al.
2000; Sajikumar and Frey 2003), mGluRs (Huber et al. 2000;
Naie and Manahan-Vaughan 2005; Nosyreva and Huber 2005),
and in this study, m1 receptors. In many studies, expression of
plasticity 1 h after induction requires new protein synthesis for
its maintenance (Linden 1996; Sajikumar and Frey 2003);
others have shown that transmission returns to baseline within
minutes after termination of the inducing stimulus, when protein synthesis is prevented pharmacologically (Huber et al.
2000; Nosyreva and Huber 2005). Not all forms of long-term
plasticity, however, require protein synthesis for expression.
For instance, the expression of mGluR-dependent LTD in
neonatal rats, induced either by application of R, S-dihydroxyphenylglycine (DHPG) or using paired-pulse-LFS, is protein
synthesis independent (Nosyreva and Huber 2005). In addition,
some forms of NMDAR-dependent LFS LTD induced in vitro
(Huber et al. 2000) and AP4-induced mGluR LTD in vivo
(Naie and Manahan-Vaughan 2005) do not require protein
synthesis for their expression.
Although this study does not identify the proteins being
translated that are required for long-term expression of mLTD,
there are several candidates. It is unclear whether or not
required proteins would undergo cap-dependent or cap-independent translation. A major pathway to cap-dependent translation is through mTOR, which according to our results is not
involved in mLTD. However, ERK, which is required for
mLTD, has also been implicated upstream of cap-dependent
protein synthesis (Klann et al. 2004), indicating that proteins
involved could undergo cap-dependent protein synthesis. One
potential protein is Arc/Arg3.1, which has been shown to be
upregulated after activation of mAChRs and the downstream
effector Src kinase (Teber et al. 2004), and has also been
shown to be capable of being translated in both a cap-dependent or cap-independent manner (Pinkstaff et al. 2001). In
addition, Arc is involved in AMPAR internalization and implicated in keeping these receptors sequestered from the
plasma membrane (Chowdhury et al. 2006; Shepherd et al.
2006) both of which are well-established mechanisms for LTD
expression (Anwyl 2006; Malenka 2003). Interestingly, Arc
mRNA has been shown to rapidly localize to activated den-
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which may or may not involve PKC activation, or a member of
the family of Src kinases, or possibly some cooperation between these two pathways (Puente et al. 2000; Rosenblum et al.
2000). Complete blockade of mLTD by a Src kinase inhibitor
combined with the modest inhibition of LTD during blockade
of PLC suggests that ERK1/2 activation may occur through
convergence of these two pathways. However, because a significant level of LTD is still observed during PLC inhibition,
our data suggest that the predominant pathway responsible for
ERK1/2 activation involves Src kinases, with a limited requirement for PLC and no requirement for PKC. The partial requirement of PLC in mLTD induction we find in visual cortex
is in contrast to mLTD we have observed at CA3–CA1 synapses (Scheiderer and McMahon 2004), where only Src kinase
and ERK1/2 are required. Our finding of a partial role for PLC
in mLTD induction fits well with recent studies that showed
that NMDAR-dependent LTD at synapses induced with low
frequency stimulation (LFS-LTD) in layer 2/3 also requires
PLC activation (Choi et al. 2005; Origlia et al. 2006). Specifically, in studies by Origlia et al. (2006), activation of PLC was
reported to occur through stimulation of m1 receptors alone,
whereas Choi et al. (2005) showed that PLC activation occurs
through cooperative activation of several G␣q coupled receptors, specifically m1 receptors, ␣1 adrenergic receptors, and
group I metabotropic glutamate receptors (mGluRs). Origlia et
al. (2006) also found that blocking mAChRs with atropine was
sufficient to block LFS-LTD, and we have made this same
observation (upublished observations). On the other hand, Choi
et al. (2005) found that inhibition of LFS-LTD required simultaneous blockade of mAChRs, mGluRs, and adrenergic receptors. Whether ERK1/2 activation is downstream of PLC activation or if the Src kinase family is also involved in LFS-LTD,
similarly to mLTD, was not investigated in these studies.
Although we show here that LTD at synapses in visual cortex
induced by CCh application is not NMDAR dependent (which
is in contrast to previous reports; (Kirkwood et al. 1999), our
findings together with those of Choi et al. (2005) and Origlia et
al. (2006), showing that the requirement of PLC activation for
LTD induction can be fulfilled through different Gq coupled
receptors, suggest the possibility of a convergence of mechanisms activated by NMDARs with those activated by G␣q
coupled receptors to induce LTD. In future studies, it will be
important to determine whether saturation of LTD induced by
LFS will occlude or prevent further LTD induced by pharmacological activation of m1 receptors, which should occur if the
NMDAR-dependent and -independent mechanistic pathways
converge downstream. Unlike our findings in visual cortex, our
studies of mLTD at CA3-CA1 synapses in hippocampus
showed that this LTD is NMDAR dependent (Scheiderer et al.
2006) and its induction can be occluded by prior saturation of
LFS-LTD, which is also NMDAR dependent (McCutchen et
al. 2006).
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P. A. McCOY AND L. L. McMAHON
drites (Chowdhury et al. 2006), further supporting a role in
long-term expression of plasticity requiring protein synthesis.
Additional possibilities are proteins that regulate CREB activity, because this molecule has been shown to be required for
the long-term maintenance of cerebellar and hippocampal LTD
(Ahn et al. 1999; Yang et al. 2003) and has been shown to be
activated by mAChR stimulation (Zhao et al. 2003). The
potential role of Arc and/or CREB in long-term maintenance of
mLTD awaits future study.
Cholinergic modulation, synaptic plasticity, and learning
and memory
GRANTS
This work was supported by National Institutes of Health Grants AG-21612
to L. L. McMahon and F31 NS-56835 to P. McCoy and by T32 EY-007033
and National Institutes of Health Neuroscience Blueprint Core Grant NS57098.
REFERENCES
Ahn S, Ginty DD, Linden DJ. A late phase of cerebellar long-term depression
requires activation of CaMKIV and CREB. Neuron 23: 559 –568, 1999.
J Neurophysiol • VOL
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Cholinergic innervation is essential for learning and memory
dependent on cortical function and plasticity. Deficits in cortical cholinergic function often cause substantial cognitive
impairments (Perry et al. 1999; Sarter and Bruno 1998), and
mAChRs, specifically m1 receptors, have been implicated in
cholinergic dependent cognitive processes (Anagnostaras et al.
2003; Bodick et al. 1997; Ghelardini et al. 1999; Sato et al.
1987a). During disease states such as Alzheimer’s disease
(AD), Rett syndrome, and schizophrenia (Ladner et al. 1995;
Liao et al. 2003; Mancama et al. 2003; Percy 1993; Satlin et al.
1997), m1 receptor signaling is decreased, which is believed to
be causal to memory deficits. In fact, recent studies have shown
that m1 agonists relieve cognitive impairments, vocal outburst,
and hallucinations associated with AD (Bodick et al. 1997;
Fisher et al. 2003). In rodents, knockdown or knockout of m1
receptors impairs memory formation (Anagnostaras et al.
2003; Caccamo et al. 2006; Ghelardini et al. 1999), whereas in
humans, infusion of muscarinic antagonists hinders memory
driven tasks (Rosier et al. 1999). Because mLTD requires
activation m1 receptors, it may serve as a mechanism by which
acetylcholine modulates learning and memory.
It has been reported that cholinergic neurotransmission is
required in recognition memory (Warburton et al. 2003), as
well as in the induction of LFS-LTD in numerous areas of the
CNS (Choi et al. 2005; Li et al. 2005; Origlia et al. 2006;
Warburton et al. 2003). Thus a form of LTD dependent on
cholinergic modulation of synaptic function in visual cortex,
such as mLTD, may be critical for normal learning and memory dependent on visual system processing. This idea is well
supported by studies showing that cholinergic denervation of
visual cortex causes deficits in both LTD (Kuczewski et al.
2005) and in learning and memory, specifically an impairment
in acquisition and retention of visual discriminations (Barefoot
et al. 2002 2000; Kesner et al. 1987). The ability of m1
receptor activation to induce long-term synaptic depression at
excitatory synapses seems to be a general mechanism by which
the cholinergic system modulates glutamate synapses in many
regions of the CNS (Kirkwood et al. 1999; Massey et al. 2001;
Scheiderer et al. 2006) and may explain the cholinergic requirement for normal learning, memory, and cognition.
Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP,
Nathanson NM, Silva AJ. Selective cognitive dysfunction in acetylcholine
M1 muscarinic receptor mutant mice. Nat Neurosci 6: 51–58, 2003.
Anwyl R. Induction and expression mechanisms of postsynaptic NMDA
receptor-independent homosynaptic long-term depression. Prog Neurobiol
78: 17–37, 2006.
Banko JL, Hou L, Poulin F, Sonenberg N, Klann E. Regulation of
eukaryotic initiation factor 4E by converging signaling pathways during
metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26: 2167–2173, 2006.
Barefoot HC, Baker HF, Ridley RM. Synergistic effects of unilateral
immunolesions of the cholinergic projections from the basal forebrain and
contralateral ablations of the inferotemporal cortex and hippocampus in
monkeys. Neuroscience 98: 243–251, 2000.
Barefoot HC, Baker HF, Ridley RM. Crossed unilateral lesions of temporal
lobe structures and cholinergic cell bodies impair visual conditional and
object discrimination learning in monkeys. Eur J Neurosci 15: 507–516,
2002.
Bentley P, Husain M, Dolan RJ. Effects of cholinergic enhancement on
visual stimulation, spatial attention, and spatial working memory. Neuron
41: 969 –982, 2004.
Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A,
Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ,
Potter WZ, Paul SM. Effects of xanomeline, a selective muscarinic
receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54: 465– 473, 1997.
Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG. Mechanisms underlying rapid experience-dependent plasticity in the human visual cortex.
Proc Natl Acad Sci USA 98: 14698 –14701, 2001.
Brocher S, Artola A, Singer W. Intracellular injection of Ca2⫹ chelators
blocks induction of long-term depression in rat visual cortex. Proc Natl
Acad Sci USA 89: 123–127, 1992.
Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A,
LaFerla FM. M1 receptors play a central role in modulating AD-like
pathology in transgenic mice. Neuron 49: 671– 682, 2006.
Chan AS, Yeung WW, Wong YH. Integration of G protein signals by
extracellular signal-regulated protein kinases in SK-N-MC neuroepithelioma cells. J Neurochem 94: 1457–1470, 2005.
Choi SY, Chang J, Jiang B, Seol GH, Min SS, Han JS, Shin HS, Gallagher
M, Kirkwood A. Multiple receptors coupled to phospholipase C gate
long-term depression in visual cortex. J Neurosci 25: 11433–11443, 2005.
Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N,
Kuhl D, Huganir RL, Worley PF. Arc/Arg3.1 interacts with the endocytic
machinery to regulate AMPA receptor trafficking. Neuron 52: 445– 459,
2006.
Davis HP, Squire LR. Protein synthesis and memory: a review. Psychol Bull
96: 518 –559, 1984.
Dobrunz LE, Stevens CF. Heterogeneity of release probability, facilitation,
and depletion at central synapses. Neuron 18: 995–1008, 1997.
Drachman DA, Leavitt J. Human memory and the cholinergic system. A
relationship to aging? Arch Neurol 30: 113–121, 1974.
Dunnett SB, Fibiger HC. Role of forebrain cholinergic systems in learning
and memory: relevance to the cognitive deficits of aging and Alzheimer’s
dementia. Prog Brain Res 98: 413– 420, 1993.
Fisher A, Pittel Z, Haring R, Bar-Ner N, Kliger-Spatz M, Natan N, Egozi
I, Sonego H, Marcovitch I, Brandeis R. M1 muscarinic agonists can
modulate some of the hallmarks in Alzheimer’s disease: implications in
future therapy. J Mol Neurosci 20: 349 –356, 2003.
Fournier GN, Semba K, Rasmusson DD. Modality- and region-specific
acetylcholine release in the rat neocortex. Neuroscience 126: 257–262,
2004.
Ghelardini C, Galeotti N, Matucci R, Bellucci C, Gualtieri F, Capaccioli S,
Quattrone A, Bartolini A. Antisense ‘knockdowns’ of M1 receptors
induces transient anterograde amnesia in mice. Neuropharmacology 38:
339 –348, 1999.
Gruber T, Keil A, Muller MM. Modulation of induced gamma band
responses and phase synchrony in a paired associate learning task in the
human EEG. Neurosci Lett 316: 29 –32, 2001.
Gruber T, Muller MM, Keil A. Modulation of induced gamma band
responses in a perceptual learning task in the human EEG. J Cogn Neurosci
14: 732–744, 2002.
Hepler DJ, Wenk GL, Cribbs BL, Olton DS, Coyle JT. Memory impairments following basal forebrain lesions. Brain Res 346: 8 –14, 1985.
VISUAL CORTEX mLTD REQUIRES ERK AND TRANSLATION
J Neurophysiol • VOL
McCutchen E, Scheiderer CL, Dobrunz LE, McMahon LL. Coexistence of
muscarinic long-term depression with electrically induced long-term potentiation and depression at CA3-CA1 synapses. J Neurophysiol 96: 3114 –
3121, 2006.
Miltner WH, Braun C, Arnold M, Witte H, Taub E. Coherence of
gamma-band EEG activity as a basis for associative learning. Nature 397:
434 – 436, 1999.
Mrzljak L, Levey AI, Goldman-Rakic PS. Association of m1 and m2
muscarinic receptor proteins with asymmetric synapses in the primate
cerebral cortex: morphological evidence for cholinergic modulation of excitatory neurotransmission. Proc Natl Acad Sci USA 90: 5194 –5198, 1993.
Muller W, Misgeld U, Heinemann U. Carbachol effects on hippocampal
neurons in vitro: dependence on the rate of rise of carbachol tissue concentration. Exp Brain Res 72: 287–298, 1988.
Naie K, Manahan-Vaughan D. Investigations of the protein synthesis dependency of mGluR-induced long-term depression in the dentate gyrus of freely
moving rats. Neuropharmacology 49: 35– 44, 2005.
Nosyreva ED, Huber KM. Developmental switch in synaptic mechanisms of
hippocampal metabotropic glutamate receptor-dependent long-term depression. J Neurosci 25: 2992–3001, 2005.
Origlia N, Kuczewski N, Aztiria E, Gautam D, Wess J, Domenici L.
Muscarinic acetylcholine receptor knock-out mice show distinct synaptic
plasticity impairments in the visual cortex. J Physiol 577: 829 – 840, 2006.
Percy A. Meeting report: Second International Rett Syndrome Workshop and
Symposium. J Child Neurol 8: 97–100, 1993.
Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22: 273–280, 1999.
Pinkstaff JK, Chappell SA, Mauro VP, Edelman GM, Krushel LA.
Internal initiation of translation of five dendritically localized neuronal
mRNAs. Proc Natl Acad Sci USA 98: 2770 –2775, 2001.
Puente LG, Stone JC, Ostergaard HL. Evidence for protein kinase Cdependent and -independent activation of mitogen-activated protein kinase
in T cells: potential role of additional diacylglycerol binding proteins.
J Immunol 165: 6865– 6871, 2000.
Rodriguez R, Kallenbach U, Singer W, Munk MH. Short- and long-term
effects of cholinergic modulation on gamma oscillations and response
synchronization in the visual cortex. J Neurosci 24: 10369 –10378, 2004.
Rosenblum K, Futter M, Jones M, Hulme EC, Bliss TV. ERKI/II regulation
by the muscarinic acetylcholine receptors in neurons. J Neurosci 20:
977–985, 2000.
Rosier AM, Cornette L, Dupont P, Bormans G, Mortelmans L, Orban
GA. Regional brain activity during shape recognition impaired by a scopolamine challenge to encoding. Eur J Neurosci 11: 3701–3714, 1999.
Sajikumar S, Frey JU. Anisomycin inhibits the late maintenance of long-term
depression in rat hippocampal slices in vitro. Neurosci Lett 338: 147–150,
2003.
Sarter M, Bruno JP. Age-related changes in rodent cortical acetylcholine and
cognition: main effects of age versus age as an intervening variable. Brain
Res Brain Res Rev 27: 143–156, 1998.
Satlin A, Bodick N, Offen WW, Renshaw PF. Brain proton magnetic
resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after
treatment with xanomeline, an M1 selective cholinergic agonist. Am J
Psychiatry 154: 1459 –1461, 1997.
Sato H, Hata Y, Hagihara K, Tsumoto T. Effects of cholinergic depletion on
neuron activities in the cat visual cortex. J Neurophysiol 58: 781–794,
1987a.
Sato H, Hata Y, Masui H, Tsumoto T. A functional role of cholinergic
innervation to neurons in the cat visual cortex. J Neurophysiol 58: 765–780,
1987b.
Scheiderer CL, McCutchen E, Thacker EE, Kolasa K, Ward MK, Parsons
D, Harrell LE, Dobrunz LE, McMahon LL. Sympathetic sprouting drives
hippocampal cholinergic reinnervation that prevents loss of a muscarinic
receptor-dependent long-term depression at CA3-CA1 synapses. J Neurosci
26: 3745–3756, 2006.
Scheiderer CL, McMahon LL. Muscarinic M1 and a adrenergic 1 receptor
dependent long-term depression at CA3-CA1 synapses in rat hippocampus
requires activation of MAPK. Soc Neurosci Abstr 856.12, 2004.
Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D,
Huganir RL, Worley PF. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52: 475– 484, 2006.
Tallon-Baudry C, Bertrand O, Peronnet F, Pernier J. Induced gamma-band
98 • OCTOBER 2007 •
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 16, 2017
Himmelheber AM, Sarter M, Bruno JP. Increases in cortical acetylcholine
release during sustained attention performance in rats. Brain Res Cogn Brain
Res 9: 313–325, 2000.
Huber KM, Kayser MS, Bear MF. Role for rapid dendritic protein synthesis
in hippocampal mGluR-dependent long-term depression. Science 288:
1254 –1257, 2000.
Idzikowski C, Oswald I. Interference with human memory by an antibiotic.
Psychopharmacology (Berl) 79: 108 –110, 1983.
Ismailov I, Kalikulov D, Inoue T, Friedlander MJ. The kinetic profile of
intracellular calcium predicts long-term potentiation and long-term depression. J Neurosci 24: 9847–9861, 2004.
Karni R, Gus Y, Dor Y, Meyuhas O, Levitzki A. Active Src elevates the
expression of beta-catenin by enhancement of cap-dependent translation.
Mol Cell Biol 25: 5031–5039, 2005.
Kelleher RJ III, Govindarajan A, Jung HY, Kang H, Tonegawa S.
Translational control by MAPK signaling in long-term synaptic plasticity
and memory. Cell 116: 467– 479, 2004.
Kesner RP, Adelstein T, Crutcher KA. Rats with nucleus basalis magnocellularis lesions mimic mnemonic symptomatology observed in patients
with dementia of the Alzheimer’s type. Behav Neurosci 101: 451– 456,
1987.
Kimura F, Baughman RW. Distinct muscarinic receptor subtypes suppress
excitatory and inhibitory synaptic responses in cortical neurons. J Neurophysiol 77: 709 –716, 1997.
Kirkwood A, Rozas C, Kirkwood J, Perez F, Bear MF. Modulation of
long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J Neurosci 19: 1599 –1609, 1999.
Klann E, Antion MD, Banko JL, Hou L. Synaptic plasticity and translation
initiation. Learn Mem 11: 365–372, 2004.
Klink R, Alonso A. Muscarinic modulation of the oscillatory and repetitive
firing properties of entorhinal cortex layer II neurons. J Neurophysiol 77:
1813–1828, 1997.
Kuczewski N, Aztiria E, Leanza G, Domenici L. Selective cholinergic
immunolesioning affects synaptic plasticity in developing visual cortex. Eur
J Neurosci 21: 1807–1814, 2005.
Ladner CJ, Celesia GG, Magnuson DJ, Lee JM. Regional alterations in M1
muscarinic receptor-G protein coupling in Alzheimer’s disease. J Neuropathol Exp Neurol 54: 783–789, 1995.
Laplante F, Morin Y, Quirion R, Vaucher E. Acetylcholine release is
elicited in the visual cortex, but not in the prefrontal cortex, by patterned
visual stimulation: a dual in vivo microdialysis study with functional
correlates in the rat brain. Neuroscience 132: 501–510, 2005.
Li H, Zhang J, Xiong W, Xu T, Cao J, Xu L. Long-term depression in rat
CA1-subicular synapses depends on the G-protein coupled mACh receptors.
Neurosci Res 52: 287–294, 2005.
Liao DL, Hong CJ, Chen HM, Chen YE, Lee SM, Chang CY, Chen H,
Tsai SJ. Association of muscarinic m1 receptor genetic polymorphisms with
psychiatric symptoms and cognitive function in schizophrenic patients.
Neuropsychobiology 48: 72–76, 2003.
Linden DJ. A protein synthesis-dependent late phase of cerebellar long-term
depression. Neuron 17: 483– 490, 1996.
Malenka RC. Synaptic plasticity and AMPA receptor trafficking. Ann NY
Acad Sci 1003: 1–11, 2003.
Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron
44: 5–21, 2004.
Manahan-Vaughan D, Kulla A, Frey JU. Requirement of translation but not
transcription for the maintenance of long-term depression in the CA1 region
of freely moving rats. J Neurosci 20: 8572– 8576, 2000.
Mancama D, Arranz MJ, Landau S, Kerwin R. Reduced expression of the
muscarinic 1 receptor cortical subtype in schizophrenia. Am J Med Genet B
Neuropsychiatr Genet 119: 2– 6, 2003.
Marino MJ, Rouse ST, Levey AI, Potter LT, Conn PJ. Activation of the
genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells. Proc Natl
Acad Sci USA 95: 11465–11470, 1998.
Massey PV, Bhabra G, Cho K, Brown MW, Bashir ZI. Activation of
muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex. Eur J Neurosci 14: 145–152, 2001.
Mayo W, Kharouby M, Le Moal M, Simon H. Memory disturbances
following ibotenic acid injections in the nucleus basalis magnocellularis of
the rat. Brain Res 455: 213–222, 1988.
McCormick DA, Wang Z, Huguenard J. Neurotransmitter control of neocortical neuronal activity and excitability. Cereb Cortex 3: 387–398, 1993.
1869
1870
P. A. McCOY AND L. L. McMAHON
activity during the delay of a visual short-term memory task in humans.
J Neurosci 18: 4244 – 4254, 1998.
Teber I, Kohling R, Speckmann EJ, Barnekow A, Kremerskothen J.
Muscarinic acetylcholine receptor stimulation induces expression of the
activity-regulated cytoskeleton-associated gene (ARC). Brain Res Mol
Brain Res 121: 131–136, 2004.
Thiel CM, Henson RN, Dolan RJ. Scopolamine but not lorazepam modulates
face repetition priming: a psychopharmacological fMRI study. Neuropsychopharmacology 27: 282–292, 2002.
Tsokas P, Ma T, Iyengar R, Landau EM, Blitzer RD. Mitogen-activated
protein kinase upregulates the dendritic translation machinery in long-term
potentiation by controlling the mammalian target of rapamycin pathway.
J Neurosci 27: 5885–5894, 2007.
Warburton EC, Koder T, Cho K, Massey PV, Duguid G, Barker GR,
Aggleton JP, Bashir ZI, Brown MW. Cholinergic neurotransmission is
essential for perirhinal cortical plasticity and recognition memory. Neuron
38: 987–996, 2003.
Wenk H, Bigl V, Meyer U. Cholinergic projections from magnocellular nuclei
of the basal forebrain to cortical areas in rats. Brain Res 2: 295–316, 1980.
Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR.
Alzheimer’s disease and senile dementia: loss of neurons in the basal
forebrain. Science 215: 1237–1239, 1982.
Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces
long-term potentiation in the hippocampus. Science 313: 1093–1097,
2006.
Yang SN, Huang LT, Wang CL, Chen WF, Yang CH, Lin SZ, Lai MC,
Chen SJ, Tao PL. Prenatal administration of morphine decreases CREBSerine-133 phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient
rat offspring. Hippocampus 13: 915–921, 2003.
Zhao WQ, Alkon DL, Ma W. c-Src protein tyrosine kinase activity is
required for muscarinic receptor-mediated DNA synthesis and neurogenesis
via ERK1/2 and c-AMP-responsive element-binding protein signaling in
neural precursor cells. J Neurosci Res 72: 334 –342, 2003.
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 16, 2017
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98 • OCTOBER 2007 •
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