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The Journal of Neuroscience, December 15, 1998, 18(24):10464-10472
Synaptic Modifications in Cultured Hippocampal Neurons:
Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell
Type
Guo-qiang
Bi and
Mu-ming
Poo
Department of Biology, University of California at San Diego, La
Jolla, California 92093
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ABSTRACT |
In cultures of dissociated rat hippocampal neurons, persistent
potentiation and depression of glutamatergic synapses were induced by
correlated spiking of presynaptic and postsynaptic neurons. The
relative timing between the presynaptic and postsynaptic spiking
determined the direction and the extent of synaptic changes. Repetitive
postsynaptic spiking within a time window of 20 msec after presynaptic
activation resulted in long-term potentiation (LTP), whereas
postsynaptic spiking within a window of 20 msec before the repetitive
presynaptic activation led to long-term depression (LTD). Significant
LTP occurred only at synapses with relatively low initial strength,
whereas the extent of LTD did not show obvious dependence on the
initial synaptic strength. Both LTP and LTD depended on the activation
of NMDA receptors and were absent in cases in which the postsynaptic
neurons were GABAergic in nature. Blockade of L-type calcium channels
with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the
activity-induced modification of central synapses and suggest that
Hebb's rule may need to incorporate a quantitative consideration of
spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.
Key words:
synaptic modification; plasticity; hippocampal neurons; LTP; LTD; correlated-activity; spike timing; spiking; Hebb's rule; Hebbian; target specificity; cell culture
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INTRODUCTION |
Repetitive electrical activity can
induce a persistent increase or decrease of synaptic efficacy in
various parts of the nervous system, commonly referred to as long-term
potentiation (LTP) and long-term depression (LTD), respectively (Bliss
and L mo, 1973 ; Levy and Steward, 1983; Siegelbaum and Kandel, 1991;
Bliss and Collingridge, 1993; Linden and Connor, 1995; Nicoll and
Malenka, 1995). Conventional protocols for the induction of LTP and LTD generally involve repetitive presynaptic stimulation at various frequencies, in some cases coupled with a steady depolarization of the
postsynaptic neuron. Such protocols have also been used in cultures of
dissociated hippocampal neurons to induce LTP (Bekkers and Stevens,
1990; Arancio et al., 1995; Deisseroth et al., 1996; Tong et al., 1996)
and LTD (Goda and Stevens, 1996; Fitzsimonds et al., 1997). In these
previous studies, however, successful induction of LTP usually involved
preincubation of the culture in tetrodotoxin or perfusion with zero
Mg2+ solution during stimulation. Recent studies in
cortical and hippocampal slices (Magee and Johnston, 1997; Markram et
al., 1997) and in slice cultures (Debanne et al., 1998) have shown that
back-propagating action potentials, when initiated at the appropriate
time during repetitive synaptic activation, are effective in inducing
persistent synaptic potentiation or depression. In contrast to the
conventional protocol, these recent studies suggest that the timing of
presynaptic and postsynaptic action potentials can play a decisive role
in determining the type of synaptic modification. In the present study,
we have fully characterized the dependence of synaptic modifications on
the relative timing of presynaptic and postsynaptic spiking. Such
quantitative study is of particular interest in view of the findings
that precise spike timing may be used to encode information in neural
networks (Hopfield, 1995; Mainen and Sejnowski, 1995; de Ruyter van
Steveninck et al., 1997; Rieke et al., 1997). Our results showed that
postsynaptic spiking that peaked within a time window of 20 msec
after synaptic activation resulted in LTP, whereas spiking
within a window of 20 msec before synaptic activation led to
LTD. A narrow transition zone of ~5 msec existed between the
potentiation and depression windows. Furthermore, we observed that the
susceptibility of these synapses to potentiation strongly depended on
their initial strength, with significant potentiation consistently
observed only in synapses with initial amplitudes of evoked synaptic
currents <500 pA. Finally, glutamatergic synapses made onto GABAergic
neurons were not susceptible to modifications by the correlated
presynaptic and postsynaptic activity, suggesting that target
cell-specific mechanisms were involved in the induction of synaptic modifications.
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MATERIALS AND METHODS |
Cell culture. Low-density cultures of dissociated
embryonic rat hippocampal neurons were prepared as described previously (Wilcox et al., 1994). Hippocampi were removed from embryonic day
18-20 (E18-20) rats and treated with trypsin for 15 min at 37°C,
followed by washing and gentle trituration. The dissociated cells were
plated at densities of 20,000-50,000 cells/ml on
poly-L-lysine-coated glass coverslips in 35 mm Petri
dishes. The plating medium was DMEM (BioWhittaker, Walkersville,
MD) supplemented with 10% heat-inactivated fetal bovine serum
(Hyclone, Logan, UT), 10% Ham's F12 with glutamine (BioWhittaker),
and 50 U/ml penicillin-streptomycin (Sigma, St. Louis, MO).
Twenty-four hours after plating, the culture medium was changed to the
above medium containing 20 mM KCl. Both glial and neuronal
cell types are present under these culture conditions. Cells were used
for electrophysiological recordings after 8-14 d in culture.
Electrophysiology. Whole-cell perforated-patch recordings
(Hamill et al., 1981; Horn and Marty, 1988; Rae et al., 1991) from two
to three hippocampal neurons were performed simultaneously, using
amphotericin B (Sigma) for perforation. The micropipettes were made
from borosilicate glass capillaries (Kimax), with a resistance in the
range of 2-4 M . The pipettes were tip-filled with internal solution
and then back-filled with internal solution containing 150 ng/ml
amphotericin B. The internal solution contained the following (in
mM): potassium gluconate 136.5, KCl 17.5, NaCl 9, MgCl2 1, HEPES 10, EGTA 0.2, pH 7.20. The external bath
solution was a HEPES-buffered saline (HBS) containing the following (in mM): NaCl 145, KCl 3, HEPES 10, CaCl2 3, glucose 8, MgCl2 2, pH 7.30. The bath was constantly
perfused with fresh recording medium at a slow rate throughout the
recording, and all experiments were performed at room temperature. The
neurons were visualized by phase-contrast microscopy with a Nikon
inverted microscope. Recordings were performed with two or three patch
clamp amplifiers (Axopatch 200B; Axon Instruments, Foster City, CA).
Signals filtered at 5 kHz using amplifier circuitry were sampled at 10 kHz and analyzed using Axoscope software (Axon Instruments). Series
resistance (10-30 M) was always compensated at 80% (lag 100 µsec). Data were accepted for analysis only in cases in which the
coefficient of variation of EPSCs or IPSCs during the control
period did not exceed 0.4 and the input resistance (100-300 M)
remained constant throughout the experiment. For assaying synaptic
connectivity, each neuron was stimulated at a low frequency (0.03-0.06
Hz) by 1 msec step-depolarization from  70 mV to +30 mV in
voltage-clamp mode, and the responses from the other neurons as well as
autaptic responses in the stimulated neuron itself were recorded. Under our recording conditions both EPSCs and IPSCs are inward currents at
resting membrane potentials (70 to 55 mV). The IPSCs had distinctly
longer decay times and more negative reversal potentials than EPSCs
(around 50 mV). Autaptic currents, when present, were observed after
the 1 msec step-depolarization in voltage-clamp mode, with a relatively
short onset latency of <3 msec. Consistent with previous reports
(Wilcox et al., 1994; Fitzsimonds et al., 1997), EPSCs and IPSCs
observed in these cultures were glutamatergic and GABAergic in nature,
respectively. As shown in Figure 1, pharmacological studies indicated
that EPSCs were mediated by the AMPA subtype of glutamate receptors,
because they were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM) (RBI, Natick, MA); IPSCs were mediated by
GABAA receptors, because they were blocked by bicuculline
methiodide (10 µM) (RBI) but not affected by CNQX. For
cell pairs that formed reciprocal and/or autaptic connections (see Fig.
1), the cell types were identified by examining the time course and
reversal potential of synaptic currents, in some cases further
confirmed by pharmacological blockade of the transmitter receptors. In
cell pairs that lacked reciprocal or autaptic connections, patch
recordings on a third neuron that received input from one or both of
the cells were performed, and cell-type identification was performed similarly.
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RESULTS |
Glutamatergic and GABAergic synapses in hippocampal cultures
Cultures of dissociated rat hippocampal neurons were prepared from
E18-20 rat embryos and used after 8-14 d in vitro.
Dual-perforated whole-cell recordings were made simultaneously from
pairs of neurons that had formed functional synaptic connections. In
many cases, reciprocal and autaptic connections were detected. The
nature of synaptic connections was determined by the time course, the reversal potential, and the sensitivity of synaptic currents to pharmacological reagents (see Methods and Materials). Figure
1A,B illustrates recordings from two pairs of neurons in these cultures. In
the first pair, both cells were glutamatergic: synaptic and autaptic
currents were not affected by bicuculline, an antagonist of
GABAA receptors, but they were completely abolished by
CNQX, a specific blocker of the AMPA subtype of the glutamate
receptors. In the second pair, cell 1 was glutamatergic, whereas cell 2 was GABAergic, as confirmed by the sensitivity of synaptic and autaptic currents produced by cell 2 to bicuculline but not to CNQX. In the
present study, we used only glutamatergic connections for which the
postsynaptic cell type had been identified.
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Figure 1.
Glutamatergic and GABAergic connections between
two hippocampal neurons in cell cultures. A, Synaptic
currents recorded from a pair of interconnected glutamatergic neurons.
Step depolarizations (+ 100 mV, 1 msec) were applied sequentially to
each neuron while EPSCs were monitored in both neurons
(Vc = 70 mV). The matrices depict sample
EPSCs recorded in either neuron (R1 or
R2) when neuron 1 (S1) and neuron 2 (S2) were stimulated sequentially (average of 5 consecutive events). The three matrices represent synaptic and autaptic
currents before and after sequential addition of bicuculline (10 µM) and CNQX (10 µM) into the culture.
Arrowheads indicate monosynaptic EPSCs that were the
focus of the present study. Calibration: 100 pA, 10 msec.
B, Synaptic currents recorded from one glutamatergic
neuron (R1) and an interconnecting GABAergic neuron
(R2). Stimulating the latter (S2) results
in IPSCs (marked by *). Three matrices represent synaptic and autaptic
currents before and after sequential addition of CNQX (10 µM) and bicuculline (10 µM). Calibration:
100 pA, 10 msec.
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Potentiation induced by positively correlated
postsynaptic spiking
We first examined activity-induced modifications of synaptic
connections between two glutamatergic neurons. Synaptic efficacy was
assayed at regular intervals by test stimulation of the presynaptic neuron (in voltage clamp) at a low frequency (0.03-0.06 Hz). To induce
synaptic changes, repetitive stimulation (60 pulses at 1 Hz) was
applied to the presynaptic neuron while both cells were held in
current-clamp to allow spiking. Figure
2A depicts results from
a synaptic connection in which the evoked EPSPs during the repetitive
stimulation were capable of initiating action potentials in the
postsynaptic cell (a "suprathreshold" connection). Measurements of
the amplitude of EPSCs revealed a persistent increase in synaptic efficacy after the repetitive stimulation. In another example shown in
Figure 2B, the amplitude of EPSPs was too small to
trigger action potentials in the postsynaptic neuron (a
"subthreshold" synapse). However, depolarizing current pulses were
injected into the postsynaptic cell to initiate spiking 5 msec after
the onset of each EPSP. Significant potentiation was also observed in
this case. Figure 2C summarizes the data from 14 excitatory
connections similar to that described in Figure
2A,B, with initial EPSC amplitude ranging from 20 to 500 pA. Of the 14 cases, 13 showed persistent potentiation in the EPSC amplitude after the repetitive stimulation. In
all of these cases, the postsynaptic action potential peaked within 15 msec after the onset of each EPSP during the repetitive stimulation. This condition is referred to hereafter as "positively correlated spiking" to characterize the temporal relationship of
postsynaptic spiking with the synaptic input. Finally, when the same
experiments were performed in the presence of D-AP-5 (25 µM), an antagonist of the NMDA subtype of glutamate
receptors, no synaptic potentiation was induced (n = 5)
(Fig. 2C). This dependence of synaptic potentiation on the
activation of NMDA receptors is similar to that found for LTP in the
CA1 region of the hippocampus and several other brain areas (Bliss and
Collingridge, 1993; Malenka and Nicoll, 1993).
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Figure 2.
Synaptic potentiation induced by repetitive
presynaptic stimulation with "positively correlated postsynaptic
spiking." A, Results obtained from a pair of
glutamatergic neurons in hippocampal culture. Data points depict the
amplitude of monosynaptic EPSCs induced by test stimuli (0.03 Hz,
Vc = 70 mV) before and after repetitive
stimulation of the presynaptic neuron (60 pulses at 1 Hz, marked by the
thick arrow), with both neurons held in current clamp.
Traces of EPSCs (average of 5-10 consecutive events) 5 min before
(left) and 20 min after (right) the
repetitive stimulation are shown above, with the 5 min trace
(dashed line) superimposed onto the latter.
Arrowheads mark the EPSCs being studied. * indicates a
polysynaptic EPSC. The EPSP (with its onset time marked by the
thin arrow) and the spike recorded during one cycle of
the repetitive stimulation are depicted by the middle
trace above. Note that each presynaptic stimulus was capable of initiating an
action potential that peaked at ~5 msec after the onset of the EPSP.
Calibration: 200 pA, 10 msec for EPSCs; 40 mV, 10 msec for EPSPs.
B, Results obtained from another pair of glutamatergic
neurons. In this case, during each cycle of repetitive stimulation, the
EPSP was subthreshold, and a depolarizing current pulse (2 nA, 2 msec)
was injected into the postsynaptic neuron after the presynaptic
activation to induce a spike that peaked at ~5 msec after the onset
of the EPSP. Calibration: 20 pA, 10 msec for EPSCs; 20 mV, 10 msec for
EPSPs. C, Summary of all experiments with positively
correlated postsynaptic spiking similar to that described in
A and B in the absence ( ,
n = 14) or presence ( , n = 5) of D-AP-5 (25 µM). Data from all synaptic
connections with initial EPSC amplitude smaller than 500 pA were
included in the analysis. The amplitude of EPSCs from each experiment
was grouped with a 3 min bin size and normalized to the mean value
(dotted line) recorded before the repetitive
stimulation. Data points represent mean ± SEM. The mean
percentage change in synaptic strength after induction was 48.4 ± 9.9% (±SEM) and 2.3 ± 4.9% (±SEM) for experiments in the
absence and presence of D-AP-5, respectively. Percentage
change of each experiment was calculated from the mean EPSC amplitude
20-30 min after the induction protocol. When compared with the
baseline value before induction, significant potentiation was observed
in the absence of D-AP-5 (p < 0.001, t test) but not in the presence of
D-AP-5 (p > 0.1, t test).
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Depression induced by negatively correlated
postsynaptic spiking
To further examine the effects of postsynaptic spiking associated
with repetitive presynaptic stimulation on synaptic efficacy, postsynaptic spiking was initiated by repetitive injection of depolarizing current pulses before the activation of
subthreshold synaptic inputs. Recording from a pair of
glutamatergic neurons is shown in Figure
3A. Repetitive initiation of
postsynaptic action potentials that peaked at 6 msec before the onset
of EPSPs resulted in a persistent reduction in the EPSC amplitude. In
addition, we observed synaptic depression of autaptic or polysynaptic
connections made onto the same neuron that was repetitively stimulated.
Figure 3B depicts one such case in which the action
potential peaked at 5 msec before the onset of the autaptic EPSP during
the repetitive stimulation. Figure 3C summarizes the results
of all experiments in which the postsynaptic action
potential peaked at 3-30 msec before the
onset of each subthreshold EPSP, a condition referred to hereafter as
"negatively correlated spiking" (n = 12, including both synaptic and autaptic connections). In contrast, when a similar set of experiments was performed in the presence of D-AP-5
(25 µM), no obvious synaptic depression was observed
(n = 5) (Fig. 3C). The activation of
NMDA receptors is therefore required for the induction
of synaptic depression, similar to that found for LTD in the CA1 region
of hippocampus (Dudek and Bear, 1992; Mulkey and Malenka, 1992).
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Figure 3.
Synaptic depression induced by repetitive
stimulation with "negatively correlated postsynaptic spiking" on
subthreshold connections. A, Results from a pair of
glutamatergic neurons that formed a subthreshold synaptic connection
(similar to that in Fig. 2B). During each cycle
of the repetitive stimulation (1 Hz, 60 sec, at the time marked by the
arrow), a depolarizing current pulse was injected into
the postsynaptic neuron to initiate an action potential that peaked at
~6 msec before the onset of each EPSP. Calibration: 100 pA, 10 msec
for EPSCs; 30 mV, 10 msec for EPSPs. B, An example of
autaptic connections in which the action potential initiated by the
current injection acted both presynaptically and postsynaptically. The
interval between the onset of the autaptic response and the peak of the action potential was ~5 msec.
Calibration: same as in A. C, Summary of all experiments
with negatively correlated postsynaptic spiking similar to that
described in A and B in the absence (,
n = 12) or presence (, n = 5) of D-AP-5 (25 µM). Data from all synaptic
or autaptic connections with initial EPSC amplitude smaller than 1 nA
were included in the analysis. Data points represent mean ± SEM.
The mean percentage change in EPSC amplitude at 20-30 min after
repetitive stimulation was 18.0 ± 3.2% (±SEM) and 2.5 ± 1.8% (±SEM) for experiments in the absence and presence of
D-AP-5, respectively. Significant depression was observed
in the absence of D-AP-5 (p < 0.001, t test), but not in the presence of
D-AP-5 (p > 0.1, t test).
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The same repetitive presynaptic and postsynaptic activation as
described in Figure 3A were also applied to
suprathreshold connections that were strong enough to
initiate postsynaptic spiking via synaptic activation. As shown in
Figure 4A, initiating
negatively correlated postsynaptic spiking by repetitive current
injections 10 msec ahead of the repetitive synaptic activation did not
result in depression in this type of synapses. Instead, synaptic
potentiation was observed. The spikes initiated by synaptic activation
had apparently exerted a dominant effect that prevented the depression attributable to the preceding spikes initiated by the current injection. Results from three experiments using this protocol are
summarized in Figure 4B.
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Figure 4.
Effect of repetitive stimulation with negatively
correlated postsynaptic spiking on suprathreshold connections.
A, Results from an experiment similar to that described
in Figure 3A, except that the synaptic activation was
capable of initiating spiking of the postsynaptic neuron. The spike
initiated by current pulse injection peaked at ~10 msec before the
onset of each EPSP during repetitive stimulation. Calibration: 100 pA,
10 msec for EPSCs; 40 mV, 10 msec for the EPSP. B,
Summary of all experiments similar to that described in
A. Data points represent mean ± SEM
(n = 3). The mean percentage change in synaptic
strength after induction was 31.9 ± 9.3% (±SEM). Significant
potentiation was observed (p < 0.05, t test).
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Dependence on synaptic strength
During the above study, we noted a consistent failure in the
induction of synaptic potentiation for connections that had EPSCs of
relatively large amplitudes. When the extent of synaptic potentiation, as indicated by the percentage change in the mean EPSC amplitude, was
plotted against the mean EPSC amplitude before the repetitive positively correlated postsynaptic spiking, a clear inverse
relationship was observed (Fig. 5).
Because of the use of log scale for initial EPSC amplitude, the fitted
line indicates that the percentage potentiation (by positively
correlated spiking) and initial EPSC amplitude have a nonlinear but
strongly inverse relationship. Potentiation occurred mostly in weak
synapses, with initial EPSC amplitude <500 pA. We have also examined
the correlation between the initial amplitude of EPSC and the extent of
synaptic depression induced by negatively correlated spiking at
subthreshold inputs. No significant correlation was observed for
connections with initial EPSC amplitudes ranging from 20 to 900 pA
(Fig. 5).
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Figure 5.
Dependence of synaptic modifications on the
initial synaptic strength. The percentage change in the EPSC amplitude
after the repetitive stimulation (1 Hz for 60 sec) was plotted against
the initial mean amplitude of EPSCs. Open circles
represent data from synapses exposed to repetitive presynaptic
stimulation with positively correlated postsynaptic spiking (data set
includes those shown in Fig. 2C). Filled
circles represent data from synapses exposed to repetitive
presynaptic stimulation with negatively correlated postsynaptic spiking
(data set includes those shown in Fig. 3C). Percentage
changes were calculated from the average EPSC amplitude 20-30 min
after the repetitive stimulation. Lines represent best
fits with linear regression between the percentage change and the
logarithm of initial EPSC amplitudes for positively correlated
(r = 0.72, p = 0.00017) and
negatively correlated (r = 0.037, p = 0.89) spiking, respectively.
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Dependence on postsynaptic cell type
In a separate set of experiments, we have studied activity-induced
modification of glutamatergic synapses onto GABAergic neurons (Fig.
1B). As shown in Figure
6A, repetitive
stimulation of the presynaptic neuron (60 pulses at 1 Hz), coupled with
postsynaptic spiking 6 msec after the onset of each EPSP, did not
result in any change in synaptic efficacy. The summary of results from
all similar experiments involving repetitive stimulation with
positively correlated spiking of postsynaptic GABAergic neurons (with
initial EPSC amplitude <500 pA) clearly indicated the absence of any
synaptic change (Fig. 6C). The average percentage change in
the EPSC amplitude 20-30 min after the repetitive stimulation was
0.3 ± 3.4% (SEM; n = 5), which was
significantly different (p < 0.001;
t test) from that found for cases using glutamatergic
postsynaptic neurons (Fig. 2C) (48.4 ± 9.9%, SEM;
n = 14). In another case (Fig. 6B), negatively correlated postsynaptic spiking was initiated (via current
injection) in the postsynaptic GABAergic neuron 16 msec before the
onset of each EPSP during repetitive stimulation (60 pulses at 1 Hz) of
a "subthreshold" synaptic input. Again no change in synaptic
efficacy was observed. The summary of all data on similar negatively
correlated spiking of postsynaptic GABAergic neurons indicates a
complete absence of synaptic depression (Fig. 6D).
The average percentage change in EPSC amplitude 20-30 min after
repetitive stimulation was 1.7 ± 2.0% (SEM; n = 4), which was significantly different (p < 0.001; t test) from that found for the corresponding cases
with glutamatergic postsynaptic neurons (Fig. 4C)
(18.0 ± 3.2%, SEM; n = 12).
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Figure 6.
Lack of synaptic modification for glutamatergic
synapses onto GABAergic neurons. A, Results from an
experiment performed in the same manner as that described in Figure
2B except that the postsynaptic neuron was
GABAergic. During each cycle of repetitive stimulation, the
postsynaptic spike peaked at ~5 msec after the onset of the EPSP.
Calibration: 100 pA, 10 msec for EPSCs; 50 mV, 10 msec for EPSPs.
B, Results from an experiment similar to that described
in Figure 3A except that the postsynaptic neuron was
GABAergic. Postsynaptic spiking was initiated 16 msec before the onset
of each EPSP. Calibration: same as in A. C,
D, Summary of all experiments with positively correlated
(C) and negatively correlated
(D) spiking similar to that described in
A and B, respectively. The mean
percentage change in the EPSC amplitude was 0.3 ± 3.4% (±SEM,
n = 5) and 1.7 ± 2.0% (±SEM,
n = 4), respectively, for C and
D, indicating no significant synaptic change
(p > 0.1, t test).
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The critical window for synaptic modifications
To determine the precise timing required for repetitive correlated
presynaptic and postsynaptic spiking to induce synaptic modifications,
we further varied the time interval between the presynaptic stimulation
and postsynaptic spiking, using the same protocol of repetitive
stimulation. In these experiments we used only subthreshold connections
on glutamatergic neurons with initial EPSC amplitude <500 pA. As shown
in Figure 7, synaptic changes showed a
strong but highly asymmetric dependence on spike timing. Potentiation
was consistently induced when the postsynaptic spikes peaked within a
time window of 20 msec after the onset EPSPs, whereas
depression was induced when the spikes peaked within a window of 20 msec before the onset of EPSPs. The ability for correlated spiking to induce potentiation or depression decreases rapidly as the
absolute value of spike timing increases, so that outside the 40 msec
window, synaptic modification was essentially absent. A narrow
transition range of ~5 msec (~ t = 0) exists between maximal
depression and the maximal potentiation at which the effect of
correlated spiking showed large fluctuation.
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Figure 7.
Critical window for the induction of synaptic
potentiation and depression. The percentage change in the EPSC
amplitude at 20-30 min after the repetitive correlated spiking (60 pulses at 1 Hz) was plotted against the spike timing. Spike timing was
defined by the time interval (t) between the onset of
the EPSP and the peak of the postsynaptic action potential during each
cycle of repetitive stimulation, as illustrated by the traces above.
For this analysis, we included only synapses with initial EPSC
amplitude of <500 pA, and all EPSPs were subthreshold for data
associated with negatively correlated spiking. Calibration: 50 mV, 10 msec.
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Dependence on Ca2+ channels
An immediate action of postsynaptic spiking is the opening of
voltage-gated Ca2+ channels. We have thus tested the
potential role of dendritic L-type Ca2+ channels
(Bolshakov and Siegelbaum, 1994; B. R. Christie et al., 1995,
1997; R. C. Christie et al., 1996; Magee and Johnston, 1995, 1997;
Johnston et al., 1996; Deisseroth et al., 1998) in the induction of
synaptic modifications induced by correlated spiking. Experiments were
performed on subthreshold inputs onto glutamatergic neurons in the same
manner as that described above, but with nimodipine (10 µM), an L-type Ca2+ channel blocker,
added to the culture before the onset of the experiment. As shown in
Figure 8, we observed a significant
increase in EPSC amplitude (27.3 ± 8.6%, ± SEM;
n = 4) after repetitive positively correlated spiking
(60 pulses at 1 Hz). The extent of potentiation appears to be lower
than that observed in the absence of nimodipine (48.4 ± 9.9%,
±SEM; n = 14), although the difference is not
statistically significant (p = 0.068;
t test). In contrast, no significant synaptic change in
EPSCs was observed (1.2 ± 1.3%, ± SEM; n = 7)
after repetitive negatively correlated spiking. We thus conclude that
Ca2+ influx through L-type Ca2+
channels may contribute to, but is not necessary for, synaptic potentiation induced by positively correlated spiking. For depression induced by negatively correlated spiking, however,
Ca2+ influx through L-type Ca2+
channels is necessary.
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Figure 8.
Differential effects of nimodipine on the
induction of LTP and LTD by correlated spiking. A,
Results from an experiment similar to that shown in Figure
2B except that the bath solution contained 10 µM nimodipine. During repetitive stimulation, the
postsynaptic spike was initiated ~5 msec after the onset of the EPSP.
Calibration: 100 pA, 10 msec for EPSCs; 30 mV, 10 msec for EPSPs.
B, Results from an experiment similar to that shown in
Figure 3A except that the bath solution contained 10 µM nimodipine. During repetitive stimulation,
postsynaptic spiking was initiated ~5 msec before the onset of each
EPSP. Calibration: 200 pA, 10 msec for EPSCs; 30 mV, 10 msec for EPSPs.
C, Summary of experiments with positively correlated
spiking similar to that in A. The mean percentage change
in the EPSC amplitude was 27.3 ± 8.6% (±SEM,
n = 4), which represents significant potentiation
(p < 0.05, t test).
D, Summary of experiments with negatively correlated
spiking similar to that in B. The mean percentage change
in the EPSC amplitude was 1.2 ± 1.3% (±SEM,
n = 7), indicating no significant synaptic change
(p > 0.2; t test).
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DISCUSSION |
In vivo studies of rat hippocampus have shown that the
temporal order of stimulation applied to the testing and conditioning pathways is crucial for the associative induction of synaptic modification (Levy and Steward, 1983). In rat brain slices and slice
cultures, back-propagating action potentials initiated in the
postsynaptic neuron by current injections at the soma in conjunction with presynaptic stimulation have been shown to induce persistent synaptic modifications (Magee and Johnston, 1997; Markram et al., 1997;
Debanne et al., 1998). A synaptic input became potentiated when it
preceded the back-propagating action potential by 10 msec and was
depressed if it arrived at 10 msec after the action potential. In
contrast, action potential initiated 100 msec before or after the
synaptic input had no effect (Markram et al., 1997; Debanne et al.,
1998). These earlier studies, however, did not provide a full
description of the timing requirement. It was not clear, for example,
whether synaptic input arriving 20 or 50 msec ahead of postsynaptic
action potentials would become potentiated. The present results
indicate a surprisingly narrow time window of 20 msec for either
potentiation or depression to be induced. The dependence of synaptic
modifications on spike timing is strikingly asymmetric and exhibits a
sharp transition of 5 msec between depression and potentiation. A
similar time window for activity-dependent synaptic modifications was
also observed recently in a developing retinotectal system in
vivo (Zhang et al., 1998). The effects of precise timing of spikes
in the presynaptic and postsynaptic neurons may be used in neural
networks to decipher information encoded in spike timing (Hopfield,
1995; Mainen and Sejnowski, 1995; de Ruyter van Steveninck et al.,
1997; Rieke et al., 1997) and to store information relating to the
temporal order of various synaptic inputs received by a neuron during
learning and memory (Gerstner and Abbott, 1997; Mehta et al., 1997)
In these cultures we found that only weak synaptic connections are
susceptible to synaptic potentiation by correlated spiking, with a
"cutoff" amplitude of ~500 pA. Larger EPSCs may represent either
higher average sizes of evoked synaptic currents at individual synaptic
contacts (boutons) made by the presynaptic neuron or a larger number of
boutons, or both. If higher amplitude represents increased efficacy of
individual boutons, then the existence of the cutoff amplitude for LTP
induction may indicate that the machinery underlying the expression of
synaptic potentiation has been saturated. For example, the probability
of presynaptic vesicular fusion or the expression of new postsynaptic
glutamate receptors may have reached the maximal level sustainable by
the cell. Because synaptic inputs that contribute to the postsynaptic
spiking fall into the "potentiation window" associated with the
spikes, spontaneous spiking activity in these cultures may have
continuously potentiated these synapses to a saturated level, resulting
in failure in the induction of synaptic potentiation in older cultures.
The cellular basis that gives rise to the critical window for the
induction of synaptic modifications remains to be determined. The
involvement of NMDA receptors in both potentiation and depression suggests that elevation of cytosolic Ca2+ is
critical in the induction process, similar to that for synapses in the
CA1 region of the hippocampus (Nicoll and Malenka, 1995). Action
potentials initiated during the critical time window after synaptic
activation but before the dissociation of glutamate from the NMDA
channel will lead to the opening of the channel (by removing the
Mg2+ block) and a localized surge of cytoplasmic
Ca2+ (Connor et al., 1994). This NMDA
receptor-mediated Ca2+ influx may also act
cooperatively with Ca2+ influx through the
voltage-dependent Ca2+ channels to induce synaptic
potentiation (Eilers et al., 1995; Yuste and Denk, 1995; Magee and
Johnston, 1997). The finding of a reduced extent of synaptic
potentiation in the presence of L-type Ca2+ channel
blocker is consistent with the latter findings. Although the off-rate
of glutamate from the NMDA receptor is much longer than 20 msec, the
requirement of multiple Ca2+ binding in the
activation of downstream effector molecules (e.g., calmodulin) could
potentially sharpen the time window of synaptic modification.
Alternatively, the dendritically expressed transient A-type
K+ channels that can be inactivated by subthreshold
EPSPs may also play a role by limiting the back-propagation of
dendritic action potentials initiated outside the potentiation window
(Hoffman et al., 1997). In the case of negatively correlated spiking,
spike-induced Ca2+ elevation attributable to opening
of Ca2+ channels before synaptic activation followed
by a low-level Ca2+ elevation attributable to
subthreshold synaptic activation may be responsible for the induction
of synaptic depression. Indeed, blocking L-type Ca2+
channels abolished the induction of LTD (Fig. 8). Interestingly, binding of glutamate to NMDA receptors is also required for the induction of LTD, although the membrane potential remained at a
relatively negative level after the spike. Taken together, our results
are consistent with the notion that spatial-temporal patterns of
postsynaptic Ca2+ elevation are critical for the
induction of synaptic changes (Lisman, 1989; Malenka et al., 1992;
Neveu and Zucker, 1996). Finally, we noted that there was a conspicuous
absence of short-term potentiation or depression in the present study.
This can be accounted for by our use of low-frequency stimulation,
because short-term potentiation or depression is known to result from
changes in the presynaptic transmitter supply after high-frequency
stimulation (Zucker et al., 1991).
The dependence of synaptic modifications on postsynaptic cell type has
been observed in the Schaffer collateral (McMahon and Kauer, 1997) and
the mossy fiber pathways (Maccaferri et al., 1998) in hippocampal
slices. In both studies, the standard protocol of high-frequency
stimulation that normally induces LTP at synapses onto pyramidal cells
either had no effect or resulted in persistent depression of synapses
onto interneurons. Our results showed that not only the induction of
LTP is target-cell specific; similar target specificity also exists for
the induction of LTD. The target specificity could result from
differences in the postsynaptic molecular machinery underlying synaptic
modifications. For example, both the  isoform of
calcium/calmodulin-dependent protein kinase II (CaMK II ) and the
Ca2+/calmodulin-dependent protein phosphatase 2B
(calcineurin) appear to be absent in the postsynaptic densities of
glutamatergic inputs onto GABAergic neurons in the cerebral cortex and
hippocampus (Stevens et al., 1994; Liu and Jones, 1996, 1997;
Sík et al., 1998). Interestingly, in parallel fiber synapses in
the cerebellum-like electrosensory lobe of the mormyrid electric fish,
where postsynaptic targets are GABAergic Purkinje-like cells, synaptic
modifications can still be induced. However, the dependence on the
temporal order of correlated presynaptic and postsynaptic spikes is
opposite to that reported here (Bell et al., 1997).
The general notion that correlated presynaptic and postsynaptic spiking
is responsible for synaptic modifications is well known as "Hebb's
postulate of learning" (Hebb, 1949; Stent, 1973; Brown et al., 1990;
Churchland and Sejnowski, 1992). Hebb's original statement "When an
axon of a cell A is near enough to excite cell B or repeatedly or
persistently takes part in firing it, some growth or metabolic change
takes place in both cells such that A's efficiency, as one of the
cells firing B, is increased"is remarkably accurate in describing
qualitatively the synaptic potentiation induced by positively
correlated spiking reported here. In the past few decades, this concept
has been generalized and formulated mathematically into various
"Hebbian rules" of synaptic modification (Bienenstock et al., 1982;
Brown et al., 1990; Churchland and Sejnowski, 1992). Although the most
commonly used ones are based on the statistical properties of
presynaptic and postsynaptic activity (e.g., activity product, activity
covariance, etc.) without considering the detailed temporal structure
of the spike patterns, a number of formulations have indeed
incorporated a factor to reflect the relative spike timing (Sutton and
Barto, 1981; Tesauro, 1986; Klopf, 1988; Herz et al., 1989; Gerstner et
al., 1993; Gerstner and Abbott, 1997). By introducing an asymmetric
temporal window into the synaptic rule, a neural network can take
advantage of this "built-in" causality/sequence detection mechanism
to naturally implement a predictive function. This is especially clear
in a network model of navigational map learning (Gerstner and Abbott, 1997), where the assumed rule of synaptic modification is very similar
to what we have observed here (Fig. 7). Our results therefore provide
both experimental support and crucial parameters for such interpretations of Hebb's rule.
| |
FOOTNOTES |
Received Aug. 13, 1998; revised Oct. 2, 1998; accepted Oct. 7, 1998.
This work was supported by grants from National Institutes of Health
(NS36999). G.B. is the recipient of a University of California President's Postdoctoral Fellowship. We thank X.-y. Wang for cell culture preparations and L. Zhang and B. Berninger for helpful discussions.
Correspondence should be addressed to Mu-ming Poo, Department of
Biology-0357, University of California at San Diego, La Jolla, CA 92093.
| |
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1615 - 1624.
[Abstract]
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L. M. Frank, G. B. Stanley, and E. N. Brown
Hippocampal Plasticity across Multiple Days of Exposure to Novel Environments
J. Neurosci.,
September 1, 2004;
24(35):
7681 - 7689.
[Abstract]
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Top
Abstract
Introduction
Compound via MeSH
