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The Journal of Neuroscience, July 2, 2003, 23(13):5503-5506
 Previous Article | Next Article 
BRIEF COMMUNICATION
Postsynaptic Density-95 Mimics and Occludes Hippocampal Long-Term Potentiation and Enhances Long-Term Depression
Valentin Stein,1
David R. C. House,1
David S. Bredt,2 and
Roger A. Nicoll1,2
Departments of 1Cellular and Molecular
Pharmacology, and 2Physiology, University of
California, San Francisco, California 94143
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Abstract
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Previous studies have shown that overexpression of the protein PSD-95
(postsynaptic density-95) selectively enhances AMPA receptor-mediated synaptic
responses in hippocampal pyramidal cells. To determine whether this effect is
related to synaptic plasticity at these synapses, we examined whether PSD-95
expression mimics long-term potentiation (LTP), and also whether it influences
LTP and long-term depression (LTD) in hippocampal slice cultures. Using
simultaneous recording from transfected or infected cells and control
pyramidal cells, we found that PSD-95, similar to LTP, increases the amplitude
and frequency of miniature EPSCs. It also converts silent synapses to
functional synapses, as does LTP. In addition, LTP is completely occluded in
cells expressing PSD-95, whereas LTD is greatly enhanced. These results
suggest that common mechanisms are involved in controlling synaptic AMPA
receptors by PSD-95 and synaptic plasticity.
Key words: PSD-95; AMPA receptors; long-term potentiation; long-term depression; hippocampus; silent synapses
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Introduction
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Recent studies have demonstrated that synaptic AMPA receptors, in contrast
to NMDA receptors, are highly dynamic. AMPA receptors cycle constitutively
into and out of the synapses. Furthermore, NMDA receptor activation can
control both the synaptic delivery and removal of AMPA receptors
(Malenka and Nicoll, 1999 ;
Ziff, 1999;
Scannevin and Huganir, 2000;
Malinow and Malenka, 2002;
Sheng and Kim, 2002).
El-Husseini et al. (2000) and
others (Ehrlich and Malinow,
2002; Beique and Andrade,
2003) have found that the protein PSD-95 (postsynaptic density-95)
regulates synaptic AMPA receptors. Expression of PSD-95 increases the number
of synaptic AMPA receptors, and this mechanism requires the interaction of
PSD-95 with the tetraspanning AMPA receptor-trafficking protein stargazin
(Chen et al., 2000;
Schnell et al., 2002). In
addition, acutely diminishing the levels of synaptic PSD-95 decreases the
number of synaptic AMPA receptors
(El-Husseini A et al., 2002).
These experiments raise the possibility that the
PSD-95–stargazin-trafficking mechanism of AMPA receptors might also play
a role in the activity-dependent changes in synaptic strength that are
initiated by NMDA receptor activation. We examined this possibility by
studying the effects of PSD-95 on the ability to induce long-term potentiation
(LTP) and long-term depression (LTD). During this study, Beique and Andrade
(2003) reported that expression
of PSD-95 enhances LTD in neurons of the cerebral cortex. In addition, Ehrlich
and Malinow (2002) reported
that expression of PSD-95 occludes LTP.
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Materials and Methods
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Rat hippocampal slice cultures were prepared as described previously
(Schnell et al., 2002).
PSD-95–GFP (green fluorescent protein)
(Schnell et al., 2002) was
expressed either by transfection with the Helios Gene Gun (Bio-Rad
Laboratories, Hercules, CA), using 1.0 µm gold particles coated with DNA
according to the protocol of the manufacturer, or by viral infection.
PSD-95–GFP was cloned into pSCA1
(DiCiommo and Bremner, 1998).
Semliki forest viral particles were produced by transfecting
pSCA1–PSD-95–GFP and pHelper in a 1:1 molar ratio into human
embryonic kidney 293 (HEK293) cells. The supernatant was harvested 36–48
hr after transfection, aliquoted, and stored at –80°C. Before
infection, the virus was activated by chymotrypsin treatment for 45 min. Virus
solution was injected near CA3 using a Nanoject (Drummond, Burton, OH).
Recordings were made from CA3 cells 2–4 d after transfection or within 2
d of infection, using 2–3 M glass electrodes filled with an
internal solution consisting of the following (in mM): 115
CsMeSO3, 20 CsCl, 10 HEPES, 2.5 MgCl2, 4
Na2-ATP, 0.4 Na-GTP, 10 Na-phosphocreatine, 0.6 EGTA, and 0.1
spermine, pH 7.2. External perfusion medium consisted of (in mM):
119 NaCl, 2.5 KCl, 2.5 CaCl2, 1.3 MgSO4, 2.7
MgCl2, 1 NaH2PO4, 26.2 NaHCO3, and
11 glucose, saturated with 95% O2 and 5% CO2, and
included 100 µM picrotoxin, 20 µM bicuculline and
5–20 µM 2-Cl adenosine to block inhibition and suppress
epileptiform activity. In the minimal stimulation experiments, release
probability was further reduced by the addition of the GABAB
receptor agonist baclofen (50 µM). This ensured that on average,
both cells received similar numbers of activated synapses. Transfected or
infected pyramidal cells were identified using fluorescence microscopy. A
tungsten bipolar stimulating electrode was placed in the stratum radiatum.
Recording electrodes were used to first establish cell-attached connections
with both a transfected or infected cell and an immediately adjacent control
cell under visual guidance (40x; differential interference contrast
optics). Both cells were broken into simultaneously, and stimulation intensity
was adjusted until EPSCs were elicited from both cells. Series resistances
were monitored during the experiment and typically ranged from8to12M. A
cell pair was discarded if the series resistances differed substantially
between the two cells. The collection and analysis of the minimal stimulation
data are as described previously (Isaac et
al., 1995). The noise amplitude distribution was estimated using
the same duration window (5–10 msec) used for measuring EPSCs, but was
performed on the trace before the stimulus. Failure rates were estimated using
the methods of Liao et al.
(1995). Briefly, the number of
responses with an amplitude of >0 pA was determined, and this value was
then doubled to produce the failure rate. The ability to generate LTP in
control cells in transfected or infected slices varied to some extent across
slices but very little from cells within the same slices. For instance,
simultaneous recording from pairs of control cells demonstrated that if one
cell showed LTP, the other cell had a >80% chance of also showing LTP
(n = 10). In addition, we compared the ability to induce LTP in
control and GFP-expressing cells. In all pairs in which the control neuron
expressed LTP, the GFP-expressing neurons also expressed LTP (n = 6).
Thus, for the LTP experiments, we selected for analysis those pairs in which
the control cell expressed LTP. For the LTD experiments, all pairs were
included for analysis. Tetrodotoxin (0.5 µM) was added to the
medium in the experiments designed to record miniature EPSCs (mEPSCs). To
increase the frequency of events, 50 mM sucrose was also added to
the medium.
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Results
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We used the hippocampal slice culture to express PSD-95 in pyramidal cells.
PSD-95 was expressed either by biolistics or by viral infection. Although no
obvious difference was found in the results for these two methods, the yield
of infected neurons with viral infection was much greater than that obtained
with biolistic transfection. In confirmation of previous results, AMPA EPSCs
were consistently larger in PSD-95-expressing cells compared with control
cells (4.1-fold ± 0.6-fold, n = 24 for transfection; 3.9-fold
± 0.4-fold, n = 21 for infection). LTP is associated with an
increase in quantal size and frequency
(Oliet et al., 1996);
therefore, if the PSD-95 enhancement involves a mechanism similar to that
underlying LTP, one might expect PSD-95 to increase the amplitude and
frequency of mEPSCs. Although PSD-95 increased the amplitude and frequency of
mEPSCs in dissociated hippocampal cultures
(El-Husseini et al., 2000),
overexpression of PSD-95 in the cerebral cortex increased the frequency but
not the amplitude of mEPSCs (Beique and
Andrade, 2003). Here, we examined the effect of expressing PSD-95
on mEPSCs in the hippocampal slice culture. The mEPSCs were collected from
control and PSD-95-expressing cells in the presence of tetrodotoxin, which
blocks action potential-dependent release. Sample superimposed records from a
control cell and a PSD-95-expressing cell
(Fig. 1A) show that
the amplitude of mEPSCs is larger in a PSD-95-expressing cell compared with a
control cell. In Figure
1B, all of the events are plotted as a cumulative
frequency distribution and show that the distribution is shifted to larger
amplitudes in the PSD-95-expressing cells. This is particularly dramatic at
the higher end of the distribution. There was also a fourfold increase in the
frequency of mEPSCs in the PSD-95-expressing cells (3.0 ± 0.5 Hz;
n = 7) compared with control cells (0.8 ± 0.2 Hz; n =
7) (Beique and Andrade,
2003).
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Figure 1. Expression of PSD-95 enhances the amplitude and frequency of mEPSCs.
A, Five superimposed sample traces showing mEPSCs from a control cell
(left) and a PSD-95-expressing cell (right). Note that there are many more
events in the PSD-95-expressing cell, and that some of the events are larger
than events recorded in a control cell. B, Cumulative frequency
distributions of the amplitudes of mEPSCs recorded from control cells (closed
circles) and PSD-95-expressing cells (open circles) (n = 7).
C, Cumulative frequency distributions of the interevent intervals of
mEPSCs recorded in control cells (closed circles) and PSD-95-expressing cells
(open circles).
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One explanation for the increase in mEPSC frequency is that PSD-95 has
added AMPA receptors to silent synapses, as is postulated to occur during LTP
(Isaac et al., 1995;
Liao et al., 1995). We directly
examined this possibility by using minimal stimulation and simultaneously
comparing the failure rate in control and PSD-95-expressing cells. As shown in
the superimposed records in Figure
2A, the failure rate is much reduced in the
PSD-95-expressing cell, and as expected, the average size of the EPSC is
greatly enhanced. To ensure that this result was not simply attributable to
the PSD-95-expressing cell receiving more synaptic inputs, we compared the
size of the NMDA component of the EPSC at positive potentials in the two cells
(Fig. 2B). In five
pairs of cells in which the NMDA component was comparable in the two cells,
the average failure rate was 82 ± 5% in control cells and 35 ±
5% in PSD-95-expressing cells.
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Figure 2. Expression of PSD-95 inserts AMPA receptors into silent synapses.
A, Ten superimposed traces showing responses to minimal stimulation
from a control cell (left) and a PSD-95-expressing cell (right). Arrows
indicate when the stimulus was delivered. Note that there are many fewer
failures, and that the responses are much larger in the PSD-95-expressing
cell. B, Averaged records of all traces at –70 and +40 mV. Note
that the NMDA component is the same in the two cells, whereas the AMPA
component is much larger in the PSD-95-expressing cell. The NMDA component was
measured 55 msec after the stimulus, as indicated by the dashed line.
C, Plots of EPSC amplitude versus trial number at –70 and +40
mV for the control cell (left) and PSD-95-expressing cell (right). D,
EPSC amplitude distribution (solid line) and noise (broken line) in the
control cell (left) and the PSD-95 expressing cell (right). See Materials and
Methods for calculating noise. E, A pair-wise comparison of the
failure rate between control and PSD-95-expressing cells. See Materials and
Methods for estimating failure rate. F, A pair-wise comparison of the
size of the NMDA EPSC recorded at +40 mV. The symbol for each pair is the same
as that used in E.
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Because the enhancement of synaptic transmission by PSD-95 shares many of
the properties associated with LTP, we examined the possibility that the
PSD-95 enhancement occluded LTP. For these experiments, we recorded
simultaneously from a PSD-95-expressing cell and a neighboring control cell.
After collecting baseline responses at 0.2 Hz for 2 min, both cells were held
at –5 mV and 120 stimuli were delivered at 2 Hz. Both cells were then
returned to their original holding potential, and the stimulation rate was
returned to 0.2 Hz. As shown in Figure
3A, the responses recorded in the cells expressing PSD-95
returned to the baseline within a few minutes after pairing, whereas
neighboring control cells exhibited robust LTP. Traces from a typical
experiment are shown in Figure
3B. None of the 10 PSD-95-expressing cells, including
five with biolistics and five with viral infection, showed any LTP. Because
loss of LTP was seen with both methods, it is unlikely that the lack of LTP is
secondary to nonspecific effects that might be related to the method of gene
delivery. Furthermore, we found that similar magnitudes of LTP were observed
in cells expressing GFP compared with control cells.
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Figure 3. Expression of PSD-95 occludes LTP. A, Graph comparing LTP recorded
simultaneously from control neurons (closed circles) and neurons expressing
PSD-95 (open circles). The number of cells for both graphs is initially 10 and
decreases to five by the end. Arrow indicates the time of pairing. B,
Sample records from a pair of neurons showing EPSCs recorded before pairing
(solid lines) and after pairing (dotted lines).
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We next examined whether expression of PSD-95 affects LTD induction.
Baseline responses were obtained for a 5 min period at 0.2 Hz stimulation.
Cells were then held at –50 mV, stimulated at 1 Hz for 10 min, and then
returned to their original holding potential. In our slice culture
preparation, LTD was very small in control cells using this protocol
(Fig. 4). However, robust LTD
was recorded in every neuron expressing PSD-95.
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Figure 4. Expression of PSD-95 enhances LTD. A, Graph comparing LTD recorded
simultaneously from control neurons (closed circles) and from neurons
expressing PSD-95 (open circles). The number of cells for the control graph is
initially 11 and decreases to six by the end of the experiments. For the graph
of the cells expressing PSD-95, the number of cells is initially 11 and
decreases to five by the end of the experiment. B, Sample records
from a pair of neurons showing EPSCs recorded before pairing (solid lines) and
after pairing (dotted lines).
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Discussion
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The present results demonstrate that delivery of AMPA receptors to the
synapse by PSD-95 shares many properties with LTP. That is, expressing PSD-95
enhances both the amplitude and frequency of mEPSCs, as has been reported
previously for LTP (Oliet et al.,
1996). This enhancement is also consistent with previous studies
of PSD-95 expression in dissociated hippocampal neurons
(El-Husseini et al., 2000). The
increase in amplitude indicates that more AMPA receptors are added to
individual excitatory synapses. The increase in frequency of mEPSCs could be
attributable to three mechanisms. First, the classical interpretation is an
increase in the presynaptic release of quanta. This interpretation cannot
explain our results, because previous studies in slice culture found no change
in either the NMDA receptor component of the EPSC or in paired-pulse
facilitation in cells expressing PSD-95
(Schnell et al., 2002;
Beique and Andrade, 2003). Both
of these parameters should change if transmitter release is enhanced. Second,
the changes could be secondary to the increased amplitude of the mEPSCs. Under
control conditions, it is reasonable to assume that a subset of mEPSCs has
amplitudes below the threshold of detection. Increasing the amplitude of
mEPSCs will shift some of this undetected population above threshold. This
mechanism could explain why the shift in the cumulative amplitude frequency
distribution is more striking at larger amplitudes. Third, expression of
PSD-95 could deliver AMPA receptors to synapses lacking AMPA receptors (i.e.,
silent synapses) (Isaac et al.,
1995; Liao et al.,
1995). Although the second mechanism may well contribute to the
increased frequency, the dramatic increase in frequency strongly suggests that
PSD-95 delivers AMPA receptors to silent synapses. It has been reported
recently that expression of PSD-95 in cerebral cortical neurons increases the
frequency of mEPSCs but not their amplitude
(Beique and Andrade, 2003).
This difference might be explained in part by the fact that the enhancement in
evoked EPSCs in the hippocampus by PSD-95 is considerably larger that that
found in the cerebral cortex.
We directly tested the unsilencing of synapses by using minimal stimulation
and comparing the failure rate between control and PSD-95-expressing cells.
Although the size of the NMDA component was the same in the cell pairs, the
failure rate was much diminished in the PSD-95-expressing cells. The fact that
the NMDA component was the same in the cell pairs rules out both a presynaptic
basis for the change in failures and a difference in the number of synapses
contacting the two cells. Thus, similar to LTP, it can be concluded that
PSD-95 inserts AMPA receptors into previously silent synapses and adds AMPA
receptors to AMPA receptor-containing synapses.
Given the close mimicry of the action of PSD-95 with LTP, we looked for an
interaction between these two forms of synaptic enhancement. Indeed,
expression of PSD-95 occluded the ability to generate LTP. This effect was
seen both with transfection and infection. In contrast to LTP, the induction
of LTD was greatly enhanced in cells expressing PSD-95. These results, along
with recent data from others (Ehrlich and
Malinow, 2002; Beique and
Andrade, 2003), are complementary to previous results in which the
targeted disruption of PSD-95 diminished LTD but enhanced LTP
(Migaud et al., 1998).
The mechanism by which PSD-95 interacts with synaptic plasticity remains to
be elucidated. Two general models can be considered. First, PSD-95 could be
directly involved in the process of AMPA receptor delivery and removal during
LTP and LTD, respectively. Although this remains a possibility, additional
experiments will be needed to determine how PSD-95 fits into the current
models of AMPA receptor trafficking during LTP and LTD. A second and equally
plausible mechanism is that the delivery of AMPA receptors to the synapse by
PSD-95 could be independent and downstream of the trafficking during LTP and
LTD. In this scenario, the loading of the synaptic membrane (both silent and
nonsilent synapses) with AMPA receptors (and perhaps associated slots) by
PSD-95 expression would leave no room for additional AMPA receptors that would
be inserted during LTP. However, this abundance of synaptic AMPA receptors
would provide a pool of receptors not previously available for removal by LTD.
Regardless of the precise mechanism, the present findings emphasize the key
role that synaptic AMPA receptors play in LTP and LTD. Furthermore, they
demonstrate that simply changing the number of AMPA receptors at the synapse
profoundly shifts the threshold balance between LTP and LTD.
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Footnotes
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Received Mar. 14, 2003;
revised Apr. 24, 2003;
accepted Apr. 28, 2003.
This research was supported by grants from the National Institutes of
Health (D.S.B. and R.A.N.), the Christopher Reeves Paralysis Foundation
(D.S.B.), the Human Frontier Research Program (D.S.B.), and the Bristol-Myers
Squibb Company (R.A.N.). V.S. is supported by a grant from the Deutsche
Forschungsgemeinschaft (Emmy Noether Programm). R.A.N. is a member of the Keck
Center for Integrative Neuroscience and the Silvo Conte Center for
Neuroscience Research. D.S.B. is an established investigator for the American
Heart Association.
Correspondence should be addressed to Roger A. Nicoll, Department of
Cellular and Molecular Pharmacology, University of California San Francisco,
San Francisco, CA 94143.
Copyright © 2003 Society for Neuroscience
0270-6474/03/235503-04$15.00/0
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Top
Abstract
Introduction
