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The Journal of Neuroscience, August 15, 1999, 19(16):6748-6754
Distinct Functional Types of Associative Long-Term Potentiation
in Neocortical and Hippocampal Pyramidal Neurons
Dean V.
Buonomano
Departments of Neurobiology and Psychology, and Brain Research
Institute, University of California, Los Angeles, Los
Angeles , California 90095
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ABSTRACT |
The response of a neuron to a time-varying stimulus is influenced
by both short- and long-term synaptic plasticity. Both these forms of
plasticity produce changes in synaptic efficacy of similar magnitude on
very different time scales. A full understanding of the functional role
of each form of plasticity relies on understanding how they interact.
Here we examine how long-term potentiation (LTP) and short-term
plasticity (STP) interact in two different cell types that exhibit
NMDA-dependent LTP: neocortical L-II/III and hippocampal CA1 pyramidal
cells. STP was examined using both paired pulses and trains of pulses
before and after the induction of LTP. In both cell types, the same
pairing protocol was used to induce LTP in the presence of an unpaired
control pathway. Pairing produced a robust increase in the amplitude of
the first EPSP both in the neocortex and hippocampus. However, although in CA1 neurons the same degree of potentiation was maintained throughout the duration of a brief stimulus train, in L-II/III neurons
relatively less potentiation was seen in the later EPSPs of the train.
Paired-pulse analyses revealed that a uniform potentiation is observed
at intervals >100 msec, but at shorter intervals there is a
preferential enhancement of the first pulse. Thus, in the cortex LTP
may preferentially amplify stimulus onset. These results suggest that
there are distinct forms of associative LTP and that the different
forms may reflect the underlying computations taking place in different areas.
Key words:
long-term potentiation; short-term potentiation; associative; hippocampus; neocortex; pyramidal
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INTRODUCTION |
Long-term changes in synaptic
efficacy have been proposed to underlie various forms of learning and
of cortical reorganization. In general, these proposals assume that a
form of associative long-term potentiation (LTP) produces an increase
in the gain of a synapse. That is, after LTP all activity flowing
through that synapse is amplified. However, research on neocortical LTP between L-V pyramidal neurons, using trains of activity, has shown that
although LTP results in the potentiation of the first EPSP of a train,
little or no potentiation of the latter EPSPs may be observed (Markram
and Tsodyks, 1996 ). If such a finding is a general feature of
neocortical LTP, it has important implications as to the role of LTP in
learning and memory. For example, it is thought that LTP between
L-II/III pyramidal neurons in the barrel cortex may underlie
experience-dependent changes in receptive fields of these neurons
measured by vibrissae stimulation (Armstrong-James et al., 1994;
Diamond et al., 1994) as well as other forms of neocortical plasticity
(Buonomano and Merzenich, 1998a). If LTP at these synapses were
to potentiate only the first EPSP of a series, it would be expected
that the expression of the new receptive fields be primarily confined
to the first of a series of stimuli.
Whether or not LTP produces a constant change in the gain of a synapse
also has important implications for the understanding of the functional
role of short-term synaptic plasticity. Short-term plasticity (STP)
refers to use-dependent changes in synaptic efficacy occurring on the
time scale of tens to hundreds of milliseconds. Among other hypotheses,
short-term plasticity has been proposed to play a role in temporal
processing (Buonomano and Merzenich, 1995; Buonomano et al., 1997). If
LTP interacts with STP, that is, alters the temporal profile of
postsynaptic responses, it would be expected to modify the temporal
selectivity of neurons. Under this scenario, LTP would not increase the
response throughout the duration of a stimulus, but rather serve to
"amplify" stimulus onset. If, on the other hand, LTP does not
interact with STP, temporal selectivity is likely to be preserved.
Figure 1 schematizes these different
instances by showing how, starting from the same initial state, two
types of LTP could lead to very different outcomes regarding the
temporal response characteristics of a neuron.
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Figure 1.
Schematic of how the interaction between LTP and
STP can effect neuronal responses to temporal stimuli. If a cell
initially exhibits some facilitation in response to a train of inputs,
LTP can result in two different scenarios. A, If the
induction of LTP does not modify the short-term facilitation, the
temporal response characteristics remain unchanged. Suprathreshold
responses will reflect the facilitation and produce a neuron that
selectively responds to prolonged inputs. B, If LTP
modifies short-term plasticity by producing proportionally larger
potentiation of the first EPSP, suprathreshold responses will favor
detection of the stimulus onset and not of the later temporal features
of a stimulus.
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The goal of the current paper was to examine the interaction between
LTP and STP at both L-II/III auditory cortex pyramidal neurons and at
CA1 hippocampal neurons. Brief trains and paired pulses were used as
measure of STP, before and after the induction of LTP. By using the
same protocol in neocortical and hippocampal experiments, we were able
to show two distinct forms of associative LTP in regard to its effect
on STP. It is shown that L-II/III pyramidal neurons exhibit a clear
interaction between LTP and STP, specifically, EPSPs following the
first exhibit relatively less potentiation. Paired-pulse stimulation
also revealed a smaller degree of potentiation of the second EPSP of a
pair for paired-pulse intervals of 50 and 100 msec, but not for
intervals of 200 and 300 msec, indicating that changes in the temporal
profile of the postsynaptic response are limited to a time scale <200
msec. In contrast to L-II/III neurons, the same induction protocol
induced LTP that was uniform across all EPSPs of a train of stimuli in hippocampal CA1 neurons. Together these results suggest that LTP and
STP may have different functional roles at different synapses and that,
in biochemical mechanisms, must be in place to regulate both LTP and
STP in an orchestrated manner.
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MATERIALS AND METHODS |
Hippocampal and auditory cortex slice experiments were performed
on 400-µm-thick slices from 18- to 30-d-old Sprague Dawley rats.
During an equilibration period of at least 1 hr, slices were submerged
in a oxygenated medium comprised of (in mM): NaCl 119, KCl
2.5, MgSO4 1.3, NaH2PO4 1.0, NaCO3 26.2, CaCl2 2.5, and glucose 10. Slices were transferred to a submerged recording chamber perfused at a rate of 2 ml/min and maintained at a temperature of
30-31°C.
Auditory cortex experiments. For auditory cortex
slices, the brain was removed and cut into two hemispheres. One
hemisphere was placed with the medial surface on an agar block, and
transverse slices were then cut starting from the posterior end. In the
rat, the auditory cortex occupies an area of ~15-20
mm2 of the dorsolateral surface of the
temporal lobe (Winer and Larue, 1987; Sally and Kelly, 1988; Cox et
al., 1992). Auditory cortex was located within two or three slices
before and after the crossing of the corpus collossum. The medial
geniculate nucleus is visible and contained within the same plane, and
can be used as a marker of the correct anteroposterior level. The
paired pathway was always from an electrode placed laterally in
L-II/III (horizontal stimulation). An unpaired pathway was also
present, to insure pathway specificity of the induction protocol and
control for nonspecific changes in recording conditions. For the
unpaired pathway, the stimulating electrode was placed either on the
opposite side of paired pathway or vertically below the recording
electrode in the L-VI/white matter border. No significant differences
were observed in the paired-pulse ratios between these two sites.
Hippocampal experiments. The hippocampus was dissected out,
and transverse hippocampal slices were cut with a vibratome.
Intracellular recordings were made from CA1 pyramidal cells. For
stimulation, bipolar electrodes were placed in the stratum radiatum
near the CA3-CA1 border and at the subicular end of the stratum radiatum.
Recording and stimulation. Intracellular recordings were
made with sharp electrodes with an impedance of 40-100 M when
filled with 3 M KAc. All experiments were done under
current clamp. Data were sampled and recorded at 10 kHz. For
hippocampal cells, penetrations were considered acceptable if the
resting potential was less than  60 mV, the input resistance was 30 M or greater, and there were overshooting action potentials. The
same criteria were used for neocortical neurons, except that the
resting potential criterion was 70 mV. Stainless steel bipolar
electrodes were used for stimulation. We favored placing the
stimulating electrodes far from the cell being recorded, in order to
use higher current intensities for stimulation (30-800 µA, duration
of 0.1 msec), since we have observed that during paired-pulse
stimulation lower intensities are more likely to result in differential
recruitment of axonal fibers.
Protocol. In both hippocampal and neocortical experiments,
three different patterns of stimulation were used: paired-pulse stimulation at 50 and 100 msec intervals and a train of 10 pulses at 40 Hz. Each pattern was applied in the above sequence with an intertrial
interval of 20 or 30 sec (the unpaired pathway was stimulated 10-15
sec out of phase with the paired pathway). In some neocortical
experiments, only paired-pulse stimulation was used (intervals of 50, 100, 200, 300, and 400 msec). For the induction of LTP, postsynaptic
depolarization (100-150 msec) was applied in conjunction with the 40 Hz train. The degree of depolarization was adjusted to elicit ~10
spikes during the 100 msec depolarization (generally requiring 2-4
nA). In cortical experiments, pairing was matched with the last five or
six pulses, and in the hippocampus depolarization was paired with
either the first ("early pairing") or last five pulses ("late
pairing"). During training the intertrial interval remained the same
(20 or 30 sec) as during testing. However, since it was previously
reported (Colino et al., 1992; my personal observation) that it
was difficult to induce LTP with a intertrial interval >20 sec, in
most of the hippocampal experiments the intertrial interval was
decreased to 10 or 15 sec during training.
Data analysis. The responses to the 40 Hz train were
analyzed before and after the induction of LTP by first averaging
traces from a cell during a 6 min window before the beginning of the induction protocol and during a 6 min window (24-30 min) after the end
of the induction protocol. In general, each average consisted of four
traces (total of 12 trials in which each of three stimulus protocols
was applied in alteration). For analysis of the average data, each
trace was averaged with the traces from other experiments, thus
allowing the visualization of the mean (and SEM) postsynaptic response
to a 40 Hz train from all cells. For calculation of the paired-pulse
ratios, the slope or amplitude of the second pulse was determined after
the subtraction of the first EPSP. Note that for the paired-pulse
plasticity analysis displayed in Figure 4, the number of cells analyzed
for the paired and unpaired pathway is different. Although both
pathways were always present, in some instances it was not possible to
obtain reliable slope measurements of the second EPSP because of
polysynaptic contamination; that is, when there was not a clear EPSP
onset that was stimulus locked.
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RESULTS |
It was first established that L-II/III auditory cortex neurons
exhibit associative LTP. Figure
2A shows an example
from a single experiment in which a stimulus train (10 pulses at 40 Hz) was used to examine STP before and after the induction of LTP. LTP was
induced by pairing the second half of the train with postsynaptic depolarization. Pairing occurred at the same interval as testing, every
30 sec. Because the first EPSPs were not paired with depolarization, it
is possible to follow the induction of LTP during the 10 min protocol.
Note that during induction the potentiation is first observed in the
first EPSP, and the later EPSPs exhibit little potentiation, even
though these are the ones explicitly being paired with depolarization.
The time-series plot shows that LTP lasted at least 30 min and was
specific to the paired pathway. Figure 2B shows the
average LTP (as measured by the first EPSP) from 11 experiments.
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Figure 2.
Induction of LTP in a L-II/III pyramidal neuron.
A, Example of the induction of LTP by pairing
depolarization with presynaptic activity. The top trace
shows the postsynaptic response to 10 pulses (40 Hz) before training
(11 min). Subsequent traces show the responses during and after
induction of LTP. During the induction protocol, depolarization was
paired with the latter half of the 40 Hz train. The baseline trace is
repeated for comparison at each point (gray). The
bottom panel shows the slope of the first EPSP during
the paired and unpaired pathway. B, Average LTP from 11 experiments in L-II/III pyramidal neurons.
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Figure 3 shows the average interaction
between LTP and STP in L-II/III pyramidal neurons. Traces represent the
average postsynaptic responses from seven different experiments. In the
average traces it can be seen that the potentiation seemed to be larger
for the first EPSP. By scaling the first EPSP of the baseline trace to the first EPSP of the posttest trace, it is possible to see that the
amplitude of the second to fifth EPSPs is bigger during baseline, indicating relatively less potentiation of the latter EPSPs. The subtraction of the baseline from the posttest trace also reveals a
larger degree of absolute change in the first peak. Note that in the
scaled traces, the last three EPSPs overlap with the baseline. The
subtracted traces show that although these individual EPSPs underwent
little potentiation, there was a small increase in a slower DC
component. Because all studies were done under intact pharmacology, it
is possible that this steady state increase was caused by a decrease in
inhibition.
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Figure 3.
Interaction of LTP and STP in L-II/III neurons.
A, Each trace represents the average response of seven
neurons to the 40 Hz train before (black) and after
(gray) the induction of LTP. The thin
lines represent the SEM of the average trace. The middle
traces are the same as those displayed above after scaling the
first EPSP of the baseline response to the first EPSP of the posttest
response. Note that for the second to fifth EPSPs the baseline
responses are larger, indicating relatively less potentiation of these
EPSPs. The bottom trace shows the subtraction of the
baseline from the posttest trace. B, Average
postsynaptic responses to the unpaired pathway in the same seven
cells.
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To determine the time window in which the interaction between short-
and long-term plasticity is observed, we examined STP plasticity using
paired pulses of 50, 100, 200, and 300 msec. Figure
4A shows the responses
of a single cell to paired pulse before and after the induction of LTP.
Figure 4B shows the average paired-pulse plasticity
before and after LTP. As expected both paired-pulse facilitation (PPF)
and paired-pulse depression (PPD) were observed in L-II/III neurons. On
average, PPF was observed at 50 msec, and PPD was observed at longer
intervals. After the induction of LTP, the small degree of PPF observed
at 50 msec was decreased to the extent of becoming PPD. Similarly for
the 100 msec interval, there was a decrease in the paired-pulse ratio. In contrast, at intervals of 200 and 300 msec, no significant changes
in paired-pulse plasticity were observed. Figure 4, C and
D, shows that no changes were observed for the control
pathway. There was no significant difference of the baseline
paired-pulse ratios between the paired and unpaired pathways. The
paired-pulse results emphasize that changes in inhibition are unlikely
to be contributing to the observed interaction between LTP and STP. The
small increase in the steady state ("DC component") to the train
could be in part caused by a decrease in the strength of fast or slow
IPSPs. However, to produce and apparent decrease in EPSP amplitude of
the latter pulses, an increase in inhibition would be necessary.
Furthermore, at an interval of 100 msec, it is unlikely that the fast
IPSP would effect the slope of EPSPs.
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Figure 4.
LTP modifies paired-pulse plasticity in L-II/III
neurons. Traces from a single experiment before (black)
and after (gray) the induction of LTP in the
paired (A) and unpaired (C)
pathways. Right panels, Average paired-pulse ratio
(slope of the second pulse/slope of first pulse) before and after the
induction of LTP for the paired (B) and unpaired
(D) pathways. In B, each point
represents an average of 15, 15, 6, and 6 cells for the four different
intervals (in ascending order). The values of 50 and 100 msec are
significantly different before and after LTP (p < 0.02). In
D, the number of cells for each point was 12, 12, 8, and
8. Note that in A the apparent facilitation at 50 msec
is mostly temporal summation. The paired-pulse ratios shown in
B and D are calculated from the slopes of
the second EPSP after subtraction of the first EPSP.
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The results presented above clearly show that LTP produces changes in
STP in L-II/III pyramidal neurons. To determine if this is a general
feature of associative LTP, we next performed similar experiments in
hippocampal CA1 neurons. Figure
5A shows an example of a
single experiment in which paired-pulse stimulation (50 and 100 msec)
and a 40 Hz train were used to characterize STP before and after the
induction of LTP. Note that in contrast to the LTP observed in L-II/III
neurons there was clearly a large degree of potentiation of the EPSPs
occurring later in the train. Figure 5B shows the average
LTP of the first EPSP, averaged over eight different cells. The average
degree of potentiation was 180 ± 16%, as compared to the
neocortex, in which average potentiation was 158 ± 7%. Figure
5C shows that on average there was no change in PPF as the
result of the induction of LTP.
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Figure 5.
A, LTP in hippocampal CA1 pyramidal
neurons. Traces of a single experiment showing the responses to
paired-pulse stimulation at intervals of 50 and 100 msec, and a 40 Hz
train before (black) and after LTP
(gray). Note that the differences in the
amplitude of the first EPSP in the three different conditions reflect
the normal variability of synaptic amplitude. The slope of the first
EPSP is shown throughout the experiment for the paired and unpaired
pathway on the right. B, Average LTP for all eight
cells. C, Average paired-pulse ratio for the same eight
cells. There was no significant change in the paired-pulse ratio after
the induction of LTP for either the 50 or 100 msec interval.
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LTP was induced in CA1 neurons using two different protocols.
Postsynaptic depolarization was applied in conjunction with the first
(early pairing) or second half (late pairing) of the 40 Hz train. When
using extracellular stimulation to elicit a train of EPSPs, it is
possible that changes in the threshold for eliciting action potentials
in axonal fibers occur. In this scenario, STP could be contaminated by
recruitment artifacts: apparent facilitation could be caused in part by
additional axonal recruitment throughout the train. By depolarizing the
postsynaptic cell at different times, it is possible to detect if any
recruitment artifacts were consistently occurring in these experiments.
For example, if additional axons are being recruited late in the train,
they would undergo LTP with the late but not the early protocol. Thus,
different results would be obtained when comparing data from the early
and late protocol. Figure
6A shows that were no
consistent differences in the effect of LTP on STP using the two
different protocols (scaled data not shown). Figure
6B shows the pooled average traces from all eight
cells. In contrast to what was seen for the L-II/III neurons, it was
clear that potentiation appeared to be uniform throughout the duration
of the train. This is confirmed by scaling the first EPSP of the
baseline trace to that of the posttest. Scaling reveals an almost
complete overlap of all the remaining EPSPs. The subtraction trace also
reveals a clear potentiation of the later EPSPs, and that this
potentiation was a result of an increase in the amplitude of each EPSP.
Figure 6C shows that no significant changes in LTP or STP
were observed in the unpaired pathway.
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Figure 6.
In the hippocampus, LTP uniformly potentiates all
EPSPs of a train. A, Two different protocols were used
to induce LTP. Depolarization was paired either with the first five
pulses (early) or last five pulses
(late). Each trace shows the average of four separate
experiments before (black) and after
(gray) the induction of LTP. Thin
lines represent the SEM. In both groups, potentiation was
uniform across the length of the train. B, Top
traces represent the average baseline and posttest trace from
all eight cells. Middle traces are the same as those
shown above after scaling. Note that the overlap of the normalized
traces indicate potentiation was the same across all EPSPs.
Bottom trace shows the subtraction of the baseline from
the posttest traces. C, In the unpaired pathway there
were no significant changes before and after the induction of
LTP.
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DISCUSSION |
The results presented here show that the same pairing protocol
induces LTP in both CA1 and L-II/III pyramidal neurons. However, LTP
differs in relation to its effect on STP, and thus is likely to differ
in its functional consequences on neural processing. In the
hippocampus, LTP corresponds to changing the synaptic weight or gain by
a given constant: synaptic efficacy is enhanced to the same degree
irrespective of the recent activity in that synapse. In contrast, in
L-II/III neurons LTP did not reflect a constant change in the strength
of a synapse: potentiation was dependent on the recent history of
activity of that synapse. These results are the first results showing
an interaction between LTP and STP in L-II/III cortical neurons.
However, they are consistent with previous results in L-V pyramidal
neurons, which report that relatively little or no potentiation of
EPSPs occur later in a train, an effect termed redistribution of
synaptic strength (Markram and Tsodyks, 1996). Our hippocampal results
are consistent with a recent field potential (Pananceau et al., 1998)
and a whole-cell study (Selig et al., 1999) that also used brief trains
of stimulation to analyze the interaction between LTP and STP. Together
these data suggest that the LTP may be significantly different in the hippocampus and neocortex, regarding its effects on STP, and thus on
temporal selectivity. In order to understand the functional role of
neocortical LTP, it will be important to determine whether the results
observed in L-II/III and in L-V hold true at all neocortical synapses.
LTP at the thalamocortical-L-IV synapse has been described and is
known to be associative and NMDA-dependent (Crair and Malenka, 1995).
However, it is not yet known if LTP at these synapses is "CA1-like" or "L-II/III like". In the hippocampus, a clear
interaction between LTP and STP is also observed in the hippocampus at
the mossy-fiber-CA3 synapses (Zalutsky and Nicoll, 1990). However, LTP
at these synapses is generally not considered to be associative or
Hebbian in nature. Additionally, unlike CA1 and neocortical LTP
(Kirkwood et al., 1993), mossy-fiber-CA3 LTP is not
NMDA-dependent.
Short-term plasticity
It is important to note that there were baseline
differences in STP observed at L-II/III and CA1 neurons. In agreement
with previous reports, facilitation was observed in the Schaffer
collateral-CA1 synapses (Creager et al., 1980; Manabe et al., 1993;
Buonomano and Merzenich, 1996). Both facilitation and depression is
observed in neocortical synapses onto excitatory neurons (Thomson and
Deuchars, 1994; Markram and Tsodyks, 1996; Ramoa and Sur, 1996;
Stratford et al., 1996; Gil et al., 1997; Buonomano and Merzenich,
1998b; Reyes and Sakmann, 1999). However, depression seems to
predominate, and facilitation to the degree observed in CA3 is rare.
Stratford et al. (1996) have shown that part of this diversity is
determined by which neocortical synapses are involved. Reyes and
Sakmann (1999) have shown that there is also likely to be developmental changes occurring in STP. Specifically, synapses between L-II/III pyramidal neurons exhibited PPD early in development and PPF later in development.
It is unlikely that the differences in initial STP accounted for the
observed differences between hippocampus and neocortex. Often it
was the L-II/III neurons that initially exhibited the highest degree of
short-term facilitation that exhibited the largest LTP-induced changes
in STP. Furthermore, recent experiments in CA1 neurons have used
pharmacological or stimulus manipulations to decrease the initial level
of facilitation, to better resemble the baseline condition observed in
the neocortex (Pananceau et al., 1998; Selig et al., 1999). Under such
conditions, uniform LTP is still observed across the whole stimulus
train. It seems likely that neocortical synapses may exhibit more
short-term depression, precisely because LTP induced previously during
development resulted in preferential potentiation of early EPSPs, thus
producing short-term depression.
The effects of LTP on STP have generally been analyzed using
paired-pulse stimulation. Using this technique, most reports in CA1
synapses report that, on average, LTP does not effect paired-pulse plasticity (Muller and Lynch, 1988; Manabe et al., 1993; Schulz et al.,
1994), however some reports indicate that LTP produces a decrease in
PPF or a change that correlates with initial levels of PPF (Kuhnt and
Voronin, 1988; Schulz et al., 1994; Wang and Kelly, 1997). It seems
likely that brief trains of pulses would provide a more sensitive
measure of the interaction between LTP and STP, however the current
study and two others have not revealed such an interaction (Pananceau
et al., 1998; Selig et al., 1999). It is possible that differences in
the induction protocols have contributed to some of the experimental
discrepancies. In the current study, it is of interest that
depolarization during the early or late pulses did not produce
different results, suggesting that short-term facilitation is not
itself modulated in a training-sensitive manner.
Mechanistic implications
The mechanisms underlying short-term synaptic plasticity are
generally assumed to be presynaptic. Thus, LTP-induced changes in STP
have been used to argue for a presynaptic site of expression for LTP
(Kuhnt and Voronin, 1988; Schulz et al., 1994). A few recent reports
have put into question the notion that STP is a purely presynaptic
phenomenon (Clark et al., 1994; Wang and Kelly, 1996). Given our
incomplete understanding of the neural mechanisms underlying STP, it is
difficult to use the interaction between LTP and STP as evidence in
favor or against the involvement of a presynaptic site for the
expression of LTP. In the current experiments, it was observed that the
same protocol, which is assumed to rely on postsynaptic induction, does
or does not alter STP, depending on the synapses being studied. These
results emphasize the fact that biochemical mechanisms underlying LTP
must not only regulate the efficacy of synapses to isolated EPSPs, but
that specialized biochemical mechanisms are likely to be in place to
modulate short-term plasticity, whether these are presynaptic or
postsynaptic. A surprisingly large number of biochemical pathways,
particularly different kinases, have been implicated in LTP. The reason
why so many different pathways are involved with increases in synaptic
strength has remained unclear. One possibility is that such
complexity is required to maintain or alter STP in parallel with the
expression and maintenance of LTP.
Functional implications
The differential effect of LTP on STP, as well as differences in
the initial degree of short-term plasticity suggests that STP may have
multiple functional roles. Indeed, various nonmutually exclusive
hypotheses have been made regarding the role of STP in information
processing. One hypothesis is that short-term changes in synaptic
efficacy underlie temporal processing. Specifically, short-term changes
in synaptic efficacy produce time-dependent changes in the state of
local networks, which in turn result in distinct population response to
different temporal stimuli (Buonomano and Merzenich, 1995; Buonomano et
al., 1997). It has also been suggested that STP may provide a mechanism
for "on-line" modulation in certain types of behaviors (Fisher et
al., 1997). Others have hypothesized that short-term depression
between excitatory cortical neurons may play a role in gain control
(Abbott et al., 1997) or maintaining the stability of cortical circuits
by keeping positive feedback in check (Galarreta and Hestrin, 1998).
Our results indicate that because in the hippocampus LTP did not alter
the temporal profile of the postsynaptic response, LTP may be involved
in forms of learning in which preservation of temporal information is
important. In contrast, potentiation of cortical synapses results in
amplification of the onset responses, resulting in changes in the
temporal selectivity or gain control of neurons. It will be of interest
to determine whether LTD produces a converse phenomenon, increasing the
probability of neurons responding to later input events. In layer
II/III pyramidal neurons, the paired-pulse study revealed that the
interaction between short- and long-term plasticity is limited to
intervals <100-200 msec. Thus, long-term potentiation would not be
expected to alter the response profile to temporal stimuli <5-10 Hz.
This observation may reflect the segmentation time, the interval over which incoming signals are treated as independent, rather than different components of the same stimulus.
LTP of the excitatory synapses between L-II/III pyramidal neurons have
been proposed to underlie some forms of experience-dependent learning
(Armstrong-James et al., 1994; Diamond et al., 1994). Specifically,
whisker pairing (in which all but two vibrissae of a pad are removed),
results in L-II/III pyramidal neurons in the barrel cortex that exhibit
multi-vibrissae receptive fields. It has been suggested that these new
receptive fields emerge as a result of increased lateral flow of
information among supragranular pyramidal neurons as a result of LTP.
If the observations made here also apply to barrel cortex, a prediction
that emerges is that in vivo whisker pairing will result in
increased responses to the adjacent vibrissae, however, that a sequence
of whisker stimulation should reveal that the increase is limited to
the first few stimuli. Thus, in considering the functional role of LTP
in learning and memory it is necessary to take into account the effects
of LTP on short-term plasticity and whether these effects are
consistent with in vivo and behavioral data.
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FOOTNOTES |
Received March 19, 1999; revised May 21, 1999; accepted May 26, 1999.
This research was supported by the Alfred P. Sloan Foundation. I thank
Tom O'Dell for reading an earlier version of this manuscript.
Correspondence should be addressed to Dean V. Buonomano, University of
California, Los Angeles, 695 Young Drive South, Room 1320, Box 951761, Los Angeles, CA 90095.
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ABSTRACT
INTRODUCTION
