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The Journal of Neuroscience, July 15, 2000, 20(14):5312-5320
Properties and Plasticity of Paired-Pulse Depression at a
Central Synapse
Robert F.
Waldeck,
Alberto
Pereda, and
Donald S.
Faber
Department of Neurobiology and Anatomy, MCP-Hahnemann
University of the Health Sciences, Philadelphia, Pennsylvania 19129
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ABSTRACT |
Synaptic depression was studied at the axo-axonic connection
between the goldfish Mauthner axon and identified cranial relay interneurons using simultaneous presynaptic and postsynaptic recordings and a paired-pulse stimulus paradigm. We used interstimulus intervals (ISIs) ranging from 10 msec to 1 sec and a cycle time of ~5 sec. Depression ( EPSP/EPSP1) was maximal at the shorter intervals (80%)
and decreased exponentially with a  ~ 400 msec (360 ± 107 msec, mean ± SD). We found the amplitudes of the first and
second EPSP were not correlated, indicating the magnitude of depression does not depend on the amount of transmitter released by the
conditioning stimulus. At short ISIs, the latency of EPSP2 was 23%
longer than that of EPSP1 and recovered to control with ~ 400 msec, whereas rise time and decay time were not altered
significantly. The latency distribution, which is determined by the
timing of the first quantum released each trial, was used to derive
 (t), the rate of evoked exocytosis after an action potential. (t)
was biphasic, and both components were consistently delayed during
depression. Presynaptic manipulations of putative intracellular
regulatory pathways, such as Ca2+ and GTP S
injections, preferentially affected the amplitude of EPSP1 or EPSP2.
These results are not consistent with simple depletion of the available
pool of synaptic vesicles as the major mechanism underlying depression.
They rather suggest that it is attributable to a modification or
refractoriness of the release process and that there may be multiple
pathways subserving evoked exocytosis.
Key words:
paired-pulse depression; depletion; Mauthner cell; exocytosis; synaptic latency; rate of evoked transmitter release; cranial relay interneuron; secretory machinery; metaplasticity
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INTRODUCTION |
Synaptic strength is a dynamic
property such that a postsynaptic potential (PSP) exhibits short- and
long-term changes in amplitude after different patterns of use.
Long-term changes are believed to underlie learning and memory
formation (Bear and Malenka, 1994 ), whereas those that are shorter
lasting and that occur on the timescale of seconds or less play an
important role in the dynamic function of neural networks. In some
systems, one action potential leads to a decrease in the response to a
second test stimulus. Historically, this depression has been related to
depletion of the readily releasable pool of synaptic vesicles at
junctions with a high probability of release (Liley and North, 1953;
Elmqvist and Quastel, 1965; Thies, 1965; Rosenmund and Stevens, 1996;
Dobrunz and Stevens, 1997; Goda and Stevens, 1998) Alternatively,
depression may not be simply the consequence of release per se but may
instead reflect a use-dependent modification of the functional state of the molecular machinery responsible for evoked exocytosis (Betz, 1970).
The depletion hypothesis has several implications and predictions that
can be tested experimentally. Specifically, (1) when the paired-pulse
paradigm is repeatedly applied with a fixed interstimulus interval, the
degree of depression from trial to trial should be proportional to the
amount of transmitter released by the preceding stimulus, (2) there
should be no associated changes in the kinetics of release, (3)
manipulations that selectively increase the probability of release
should enhance the first response of a pair and reduce the second one,
because the conditioning stimulus will evoke more release and a greater
amount of depletion.
As part of the characterization of depression at the Mauthner (M-) axon
output connections to cranial relay interneurons (CRNs) in the goldfish
brainstem, we have tested these predictions. This connection mediates
the cranial portion of the startle reflex (Hackett and Faber, 1983),
and its general properties have been extensively characterized (Hackett
and Faber, 1983; Hackett et al., 1989). Analogous to that studied in
the hatchetfish (Auerbach and Bennett, 1969; Highstein and Bennett,
1975), it has a high safety factor associated with a high initial
probability of release, and it exhibits a robust depression, as
revealed by paired-pulse or repetitive stimulation (Hackett et al.,
1989). Because of its accessibility for presynaptic manipulation of the
release properties, along with the possibility to record simultaneously
from both presynaptic and postsynaptic elements, it is an ideal
preparation for investigating synaptic depression and its underlying
mechanisms in vivo. Our results, including an increase in
synaptic delay during depression, indicate the predictions of the
depletion hypothesis are not satisfied and suggest instead that a
change of the functional state of the exocytotic machinery is likely to
underlie depression of this central synaptic contact. We also
demonstrate that putative presynaptic intracellular regulatory pathways
modify depression in a manner inconsistent with the depletion model,
implying that the magnitude of depression itself can be modulated by
metaplastic phenomena.
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MATERIALS AND METHODS |
Electrophysiology. For this study, 60 goldfish
(Carassius auratus), 8- to 15-cm-long were perfused through
the mouth with cold tap water and immobilized with
D-tubocurarine injected intramuscularly (1-3
mg/gm, body weight). Surgical techniques were similar to those
described previously (Faber and Korn, 1978). The cranium was opened
dorsally to allow for simultaneous recordings near the midline of the
brainstem between the vagal lobes and caudal to the facial lobe. The
dura was removed above the vagal lobes, and the lobes were moved
laterally, to expose the underlying surface of the brainstem and enable
visual control of the microelectrode placement in the presynaptic
Mauthner axon. At this level of the brainstem, this unbranched
myelinated axon (60-100 µm diameter) is at most 100 µm below the
dorsal surface of the brainstem and ~150 µm from the midline (Fig.
1A). Postsynaptic
recordings were obtained from the axon of the CRN, which courses close
to the M-axon in this region and receives axo-axonic synapses from it (Hackett and Faber 1983; Hackett et al., 1989). A stimulating electrode
on the exposed caudal spinal column was used for antidromic activation
of the M-axon.
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Figure 1.
Characteristics of the excitatory axo-axonal
connection between the Mauthner axon and its postsynaptic target, the
cranial relay neuron (CRN). A,
Diagram showing the connections studied with paired intra-axonal
recordings (V) and current injections
(I) close to the site of the contact.
P, Pressure injection of neurobiotin. B,
Image of a 50 µm horizontal section of two neurobiotin-filled M-axons
(M) and a CRN axon on the right side of
the brainstem. Regions of two presumptive contact sites between the
right M-axon and the CRN are enclosed in boxes. Scale
bar, 250 µm. a, b, Higher magnification images
of the contacts shown in top and bottom
boxes of B, respectively. M-axon, Red;
CRN, blue. Scale bar, 100 µm. C, Five
superimposed records showing fluctuations in the amplitudes of EPSPs
(top, Post) evoked by single presynaptic action
potentials in the M-axon (bottom, Pre). Action potential
of M-axon occasionally evoked a full-sized spike in the CRN (peak
truncated, actual spike height = 80 mV).
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The presynaptic and postsynaptic electrodes were filled with 5 M KAc (resistance, ~8 M ) and 2.5 M KCl (resistance, ~10 M), respectively.
In some experiments presynaptic calcium concentration was increased by
pressure-injecting a 2 mM CaCl2
solution into the M-axon, further identified by the characteristic
waveform of its antidromic spike (Funch et al., 1984). The CRN was
identified by a fast EPSP evoked by a presynaptic action potential,
typically driven by a transmembrane current pulse of ~15-20 nA. All
recordings were in the current-clamp mode, and crosstalk between the
microelectrodes was minimized electronically with an Axoprobe two
electrode amplifier (Axon Instruments, Foster City, CA). Data were
recorded on line, using a Macintosh Quadra 950 computer and acquisition
software developed in the laboratory (sampling rate of 10-50 µsec)
and on tape (PCM data recorder; Vetter Instruments), and analysis was
with the same software and with procedures in Igor.
Data analysis. The analysis program measured response
amplitudes, their decay time constants (), time-to-peaks, and their onsets or latencies. The decay constant of individual EPSPs was measured assuming a monoexponential relationship, confirmed by curve
fitting averaged responses. EPSP time-to-peak was defined as the rise
time from 10 to 90% of peak value. Latency was defined as the time
from the peak of the presynaptic action potential to the onset of the
rising phase of the EPSP. The latter was measured with a computer-based
algorithm that first determines the EPSP peak and then works backwards
from the time at which the response is half-maximal toward that at
which its first derivative approaches zero. Typically, the onset was 20 µsec later than that zero slope point. In some cases, latency could
not be measured reliably because the EPSP onset was obscured by a
coupling artifact caused by crosstalk from the presynaptic current
pulse. A linear regression analysis was used to test for associations
between variables. The coefficient of determination
(r2), which indicated the
proportion of the variance of the dependent variable
attributable to covariation with the independent variable, was used to
assess the quality of the regression model (Igor Wavemetrics).
Morphology. In some experiments electrodes were filled with
a 4% solution of neurobiotin (N-(2-aminoethyl) biotinamide
hydrocloride; Vector Laboratories, Burlingame, CA) in 2.5 M KCl buffered with 10 mM
HEPES, pH 7.2. Neurobiotin was injected iontophoretically in either or
both axons, using +70 nA current pulses 400 msec in duration and
repeated at 1 Hz. After those experiments, the animal was perfused
intracardially with 4% paraformaldehyde in PBS, pH 7.4. The
brain was post-fixed, sectioned at 50 µm sections horizontally
(Vibratome), and reacted with Vectastain ABC reagent (Vector
Laboratories) for 2 hr, rinsed, and then reacted with diaminobenzidine
(DAB) to visualize the injected cells. Sections were mounted on
gelatin-coated slides and coverslipped.
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RESULTS |
Paired-pulse depression at the Mauthner-CRN connection
Every 100-200 µm the M-axon issues a short (60 µm) collateral
that terminates most often as a single ending (Fig.
1B) (Celio et al., 1979; Funch et al., 1984) having
multiple active zones (Model et al., 1975; Hackett et al., 1989). In
the caudal brainstem, some of these outputs have connections with the
axons of CRNs. The only sources of input to CRN axons are the two
M-axons, an advantage for these studies for the analysis of spontaneous
EPSPs. The junction is most likely cholinergic because we and others (Day et al., 1983) have observed that in goldfish and hatchetfish, superfusion with curare blocks the evoked and spontaneous EPSPs. Note
that this preparation has several advantages for studying paired-pulse depression (PPD), including a high safety factor, which is presumably attributable in part to high probability release sites and underlies a pronounced depression with no obvious
complications from superimposed facilitation. Finally the connection is
axo-axonic, the presynaptic and postsynaptic recording sites can be
within a few hundred micrometers of the contact zone, and both
axons have large space constants (>2 mm; Auerbach and Bennett, 1969; Funch et al., 1984). Thus, postsynaptic filtering of the EPSPs is
minimal (Faber et al., 1995, 1998).
At stimulating frequencies < 0.2 Hz, the evoked EPSP is
sufficiently large that it triggers an action potential. For our
experiments, a stimulus frequency (cycle time) of 0.5-5 Hz was used to
reduce the underlying EPSP to a subthreshold level. That is, we used frequencies that produced some steady-state depression. At those frequencies there generally was trial to trial variability in the EPSP
amplitude. These features are illustrated in Figure 1C, where examples of a spike-evoked EPSP are shown. In this case the
M-axon was stimulated at 0.3 Hz, generally producing a subthreshold EPSP whose amplitude ranged from 5 to 10 mV, and in one trial the EPSP
triggered a postsynaptic action potential. The size and duration of the
presynaptic spike were constant during this series, indicating that, as
expected, the EPSP fluctuations reflect variability in the release
process per se. The illustrated EPSP had a 0.63 msec decay time
constant and a latency of 0.27 msec, values typical for individual
responses in all experiments.
Activity-dependent depression was quantified using a paired-pulse
paradigm, with the first conditioning response being referred to as
EPSP1, and the second or test response as EPSP2. These high output
synapses depress rapidly, as revealed by the paired-pulse responses at
an interval of 20 msec in Figure
2A. In one group of
connections (n = 7) the interstimulus interval (ISI)
was progressively increased from 10 msec to 2 sec. The greatest level
of depression was observed at intervals of <100 msec (Fig.
2B), and for the illustrated experiment, recovery was
best fit by a single exponential with a time constant
(dep) of 400 msec. Overall the mean
dep was 360 ± 107 msec, with a range
from 200 to 450 msec (n = 6). Typically, recovery was
slow with little change in the degree of depression in the first 30-50
msec, as shown in Figure 2B. To achieve a large
number of paired responses per interval without concerns over
interinterval differences, the majority of experiments described here
used a fixed ISI, typically 150 msec.
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Figure 2.
Kinetic properties of paired-pulse depression.
A, Averaged recordings (n = 10) of
the EPSPs evoked in a CRN (top) by two successive M-axon
spikes (bottom) separated by an interval of 20 msec,
when depression is maximal. B, Plot of the decay of
paired-pulse depression (ordinate) as a function of interspike interval
(abscissa) in a different experiment. Each data point is an average
from  50 trials, and in this experiment the stimulus paradigm was
repeated at 2 Hz. Solid line, Best fit single
exponential; dep = 400 msec;
r2 = 0.88.
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The amplitude of EPSP2 is independent of the amplitude
of EPSP1
The first test of the applicability of depletion model to
depression at the M - axon to CRN connection was to ask if the
amplitude of EPSP2 depended on that of EPSP1. As stated above, the
model predicts that the magnitude of depression should vary from trial to trial, changing as a function of the amount of transmitter released
by the conditioning stimulus. That is, on average the size of EPSP2
should decrease as that of EPSP1 increases. For these experiments we
used a fixed ISI of either 40 or 150 msec (n = 23), and
depression typically averaged ~50%. The results in Figure
3 are characteristic of the findings
that, however, there was no relationship between the amplitudes of the
two responses. The sample records were selected to demonstrate the
same-sized depressed response could be observed for a threefold
variation in the amplitude of the conditioning EPSP (2.86-8.57 mV).
The scatterplot, from 1226 consecutive paired stimuli, demonstrates this independence and that there was sufficient variability to both
responses to permit a fair test of the hypothesis (e.g., coefficient of
variation of EPSP1, CV1 = 22%, CV2 = 32%). In
addition, the slope of the regression line is 0.03 with a
r2 value of 0.00, indicating
the relationship is not different from one with a zero slope.
Thus, the average amplitude of EPSP2 is the same when EPSP1 is large or
small. In 23 experiments, the slope ranged from  0.08 to +0.28, and
the r2 values ranged from 0.00 to 0.29. The relationship between the two EPSP amplitudes was deemed
significant in only 8 of the 23 experiments (ANOVA, p < 0.01). However, even in those eight cases, the
r2 values were low, suggesting
other factors were more significant, and the slopes were positive, that
is, the apparent relationship between the two variables was the
opposite of that expected with the depletion model. Generally there was
more variability in EPSP2 compared to EPSP1. The coefficient of
variability (CV) calculated for EPSP1 ranged from 16-41%, compared to
25-50% for EPSP2. This is consistent with a lower quantal content for
EPSP2 (Lin and Faber 1988). Overall, these findings indicate the major
prediction of the depletion model is not met at the M-axon to CRN
connection.
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Figure 3.
The magnitude of paired-pulse depression is
independent of the amount of transmitter released by a conditioning
stimulus. Left, Selected paired responses (top
traces) where the magnitude of EPSP1 varies from 2.86 to 8.57 mV, but the size of EPSP2 remains relatively constant. Bottom
trace, Typical presynaptic action potentials evoked in the
M-axon by a transmembrane depolarization pulse. The interstimulus
interval is indicated by the 150 msec bar. Right,
Scatter plot of the amplitude of EPSP2 (ordinate) versus the size of
the response to the corresponding conditioning stimulus (EPSP1). Note
that EPSP2 varies independently of trial to trial fluctuations in the
size of EPSP1. Line represents relationship generated by
simple regression analysis, with slope of 0.03 and
r2 value of 0.00. Same experiment as
in left.
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Change in kinetics of release after depression
The depletion model does not predict that depression would be
associated with changes in the kinetics of release, for example, in its
latency. However, in all cases with a fixed interstimulus interval, in
which the EPSP onset was not obscured by a coupling artifact and could
be measured reliably (n = 7), the latency of EPSP2 was
greater than that of EPSP1. This effect is illustrated in Figure
4A for two averaged
sweeps, which are overlaid temporally such that the timing of the
presynaptic spikes is the same, and the amplitude of EPSP2 is
normalized to that of EPSP1. Scaling the response to the same amplitude
is a method that avoids overestimating the latency of small-amplitude
events. The latency of a compound EPSP is a measure of the earliest
timing of exocytosis from a population of release sites (Stevens, 1968)
because the different sites are not precisely synchronized. Therefore,
histograms of measured latencies of EPSP1 or EPSP2 actually are the
distribution functions for the first release events, and an increase in
latency during paired-pulse depression could be attributable to a lower probability of occurrence of short-latency events (i.e., altered sampling from the same population of release times) or a shift to a new
distribution. In the experiment of Figure 4B, the
mean latency of EPSP2 is 29% longer than that of EPSP1, and the
latency distribution shifts to the right with the longer latency values generally not being present in the distribution of EPSP1 latencies. This shift to the right in the latency histogram suggests there is a
population of delayed release events during depression. Measurements of
individual traces showed the average latency of EPSP2 was significantly longer than that of EPSP1 (lat1 = 0.35 ± 0.04 msec;
lat2 = 0.43 ± 0.05 msec; p < 0.01;
n = 6; Table 1), with the
mean for EPSP2 being 23% longer than that of EPSP1. In addition, in
six of the seven experiments in which ISI was varied systematically,
latency 2 was significantly greater than latency 1, with the overall
mean difference being 22% (n = 7; lat1 = 0.32 ± 0.03 msec; lat 2 = 0.39 ± 0.07 msec;
p < 0.01).
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Figure 4.
Paired-pulse depression is associated with an
increase in the latency of transmitter release. A,
Top, Superimposed averaged records
(n = 8) of EPSP1 (dashed line) and
EPSP2 (solid trace), with the latter scaled in amplitude
to match the size of EPSP1. Between solid and
dashed vertical lines, Latency of average EPSP1. Between
two solid vertical lines, Latency of average EPSP2. The
interval between the two stimuli was 150 msec. Bottom
traces, Superimposed averaged M-axon action potentials that
evoked the two responses. B, Histogram of the latency
population of EPSP1 and EPSP2 evoked by stimulation of the M-axon at
1.4 Hz and with a 150 msec ISI. n = 564 pairs of
responses from a different experiment than in A. Note
shift to the right of latency values during depression (EPSP2,
solid outline) indicating longer latency values, with a mean of
0.49 ± 0.09 msec. compared to the latency of EPSP1 (dashed
outline), 0.38 ± 0.05 msec.
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The magnitude of the increase in EPSP latency during PPD was
directly related to the interstimulus interval, as illustrated by the
averaged recordings in Figure
5A for intervals from 10 to
350 msec. In this experiment, latency 2 was 0.52 msec at the shortest
interval and decreased to 0.34 msec at the longest interval shown (the
latencies of the corresponding conditioning responses were 0.35 and
0.29 msec, respectively). When the data from seven experiments were
grouped on the basis of long (>100 msec) and short (10-100 msec) ISI,
there was a clear decrease in the latency of EPSP2 at longer intervals,
although the latency was still longer than that of EPSP1, as
illustrated in Table 2. Because latency measurements from individual traces are subject to uncertainty associated with instrumental noise, we also determined the latency of
the averages of all the responses at a given ISI, thereby reducing the
signal-to-noise ratio, and the results were similar to those obtained
with measurements from individual traces (data not shown). Finally,
support for the conclusion that the increased latency of EPSP2 relative
to that of EPSP1 is a function of the interval length was obtained by
plotting the difference between the respective averages, or the latency
differential, versus ISI. The results from the M-axon-CRN connection
of Figure 5A are shown in 5B1, and they are
characteristic of the finding that the latency differential decreased
as an exponential (Lat = 125 msec) function of
ISI. The data were not fit in this manner in other experiments,
although it was clear that the latency differential decreased as the
ISI increased.
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Figure 5.
Latency differential between EPSP1 and EPSP2 is
related to the interspike interval and to the magnitude of depression.
A, Top, Superimposed averaged records
(n > 20) of EPSP2 at the indicated intervals (10, 75, and 350 msec) and of EPSP1 at 350 msec (dashed
response). Bottom traces, Superimposed averaged
M-axon action potentials that evoked the CRN responses. Decay of EPSPs
truncated. Dashed line, Baseline. B1,
Plot of relationship between the ISI (abscissa) and the averaged
latency difference (ordinate) between EPSP2 and EPSP1, for a different
experiment. Solid line is exponential fit to decay
phase, Lat = 125 msec. Data points represent
averages of latency measurements (n > 20) for each
interval. B2, Plot of relationship between the magnitude
of depression (abscissa) and the averaged latency difference
(ordinate). Linear regression (solid line) has a slope
of 0.20, with r2 = 0.79 (p < 0.01). Each data point represents an
average of latency measurements (n > 20) for
averaged depression in 0.1 bins. Same experiment as
B1.
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In addition to its inverse relationship to interval length, the
latency differential was proportional to the magnitude of depression.
When the average latency differential was plotted against the average
magnitude of depression, the two grew in parallel (Fig.
5B2). Specifically, these two parameters were linearly
related (r2 value = 0.79;
p < 0.01), and there was almost no difference between the latencies of conditioning and test EPSPs at the lowest level of
depression (0.2 in Fig. 5B2). This relationship is not
predicted by the depletion model and rather suggests that there is a
modification of the release machinery after the conditioning response.
In contrast to the latency differential of EPSPs during PPD, two other
kinetic parameters, the time constant of decay of EPSPs () and
time-to-peak (TTP), were not related to the magnitude of
depression or the ISI. In the CRN, EPSPs are fast and not shaped by the
membrane time constant (<50 µsec; Auerbach and Bennett, 1969;
hatchetfish). These EPSPs decay with one or more exponentials, the
dominant time constant being in the range of 1.32 to 1.41 msec for the
first response and 1.18 to 1.60 msec for the second response. In
neither the variable ISI groups nor the fixed ISI group was the overall
mean of the decay time constant of EPSP1 found to be significantly
different than that of EPSP2, although individual experiments did show
significant differences in the mean values of the decay constants.
Similarly, the overall mean time-to-peak of EPSP2 was not significantly
different than that of EPSP1 (TTP1 = 0.74 ± 0.14 msec;
TTP2 = 0.73 ± 0.16 msec; n = 7 fixed ISI group).
Estimating the release rate after an action potential
Stevens (1968) derived the rate of evoked exocytosis after an
action potential, (t), from the distribution of first
latencies, dS/dt, at a connection that has a
quantal content >1.0. Specifically (t) = (dP(0,t)/dt)/P(0,t),
where P(0,t) is the probability that no quanta
have been released at time t. Then
P(0,t) = 1 S(t), where S(t) is the
cumulative latency distribution. Therefore (t) = (dS/dt)/(1 S(t)).
We have calculated (t) from the distribution of first
latencies, and the corresponding cumulative histogram, in six
experiments, to determine the waveform of the release rate. For this
purpose, data were redigitized, using sampling rates of 5-10 µsec.
The results confirm the shift in latency, and they reveal a biphasic
release rate, as illustrated in Figure 6,
A and B, for two different experiments. In both
examples, the control waveform of (t) starts at ~0.21
msec after the peak of the presynaptic action potential, appears to
rise slowly to an initial peak at ~0.3-0.4 msec, and rises steeply
to a second peak in another 100-200 µsec before falling sharply to
zero. This waveform, which can be characterized by an early "foot"
followed by a sharp peak, is typical of all experiments analyzed with
this technique. Furthermore, the effect of depression on
(t) is striking, because both components are delayed
(Fig. 6A,B). Table 1 compares the shift in mean EPSP latency in these six experiments during depression with the increase in
the timing of the peak of (t); whereas mean latency
increased by 80 ± 10 µsec, the shift in the time at which
(t) was maximal was twice that, namely 170 ± 50 µsec. These results confirm the observed shift in latency and
indicate the delay in the release rate is even greater then suggested
from the latency distribution itself.
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Figure 6.
The derived release rate is delayed during
depression. A, B, Plots, from two experiments, of
(t) for both EPSP1 (solid line)
and EPSP2 (dashed line), as calculated from the
probability density for synaptic delays and the corresponding
cumulative distribution. Open and filled
arrows denote the early phase, or foot, and the peak of the
second phase of (t), respectively. Note that
both phases are delayed during depression (EPSP2 vs EPSP1) and that the
temporal separation of the two is increased. In A, bin
size = 30 µsec; n = 1357. In
B bin size = 40 µsec; n = 400.
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Plasticity of paired-pulse depression: further evidence for the
independence of EPSP1 and EPSP2
If synaptic depression is primarily attributable to depletion,
manipulations that alter the amount of transmitter released by a
conditioning stimulus would have predictable effects on the size of
EPSP2, and hence, on the depression. On the other hand, if the dominant
factor were a functional change in the exocytotic machinery per se, it
should be possible to modulate depression by differentially regulating
the magnitudes of the successive responses in a pair. To test these two
alternatives, we examined the effects of two common messengers or
intermediates in signaling cascades, namely intracellular
Ca2+, which usually signals
activity-dependent changes (Nicoll et al., 1994), and heterotrimeric
G-proteins, which often mediate the presynaptic effects of substances
that modulate transmitter release (Hille, 1992). First, in seven
experiments in which a fixed ISI (150 msec) was used, 2 mM
CaCl2 was pressure-injected into the M axon.
Elevating internal Ca2+ produced a marked
increase in the amplitude of EPSP1, as expected. If this enhancement
were attributable to a simple increase in release probability without
modifying the size of the available pool, the depletion model would
predict a corresponding reduction in the magnitude of EPSP2, with
greater depression. However, both EPSPs increased in amplitude. This
effect is illustrated in Figure 7A for averaged recordings of
EPSP1 (solid line) and EPSP2 (dashed line) before
and after injection, and in both panels the conditioning and test
traces are overlaid temporally so that the timing of the presynaptic
spikes is the same. Note that the two responses did not increase by the
same relative amounts. Rather, ~15 min after calcium ion injection,
the size of the illustrated EPSP2 had increased by 80%, compared to a
50% increase in EPSP1. Figure 7B1 illustrates the time
course of the Ca2+ effect in this
experiment and that the percentage of increase in EPSP2 was larger than
that in EPSP1, a finding in all of the experiments (Table
3). When the average size of EPSP2 at the conclusion of the recording session for each experiment (last 20 traces) was compared to the average control (20 traces before injection) there was a 67 ± 36% increase, significantly greater than the 42 ± 27% increase in the magnitude of EPSP1
(p < 0.05; n = 7; Table 3). As
illustrated in Figure 7B1, the enhancement of amplitude
typically began immediately after the injection, grew steadily during
the next 10-15 min, and lasted for the remainder of the recording
period (the longest duration being 30 min after injection). Such a
large increase was never seen in control conditions, although great
variability was observed in both responses. For comparison, the panel
in Figure 7C shows the temporal history of EPSP1 and EPSP2
amplitudes in a control experiment with no Ca2+ in the presynaptic electrode. In this
case, the response amplitudes measured after 30 min of recording with
no injection were slightly less than at the beginning of the
experiment. Overall, in the control experiments, EPSP1 and EPSP2, at
comparable recording times, averaged 99.2 ± 12% and 93.2 ± 8% of the initial values, respectively (n = 5). In
contrast to the change in amplitude after calcium injection, there was
no change in latency of either response when compared to their control
values.
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Figure 7.
Evidence that presynaptic Ca2+
injection preferentially enhances the amplitude of EPSP2. A,
Left and right, Superimposed averaged paired
responses (n = 10), presynaptic spikes
(below), and first (solid line) and
second (dashed line) EPSPs (top) obtained
before and after 2 mM Ca2+ injection,
respectively. M-axon was stimulated at 1 Hz with an interval of 150 msec. B1, Amplitudes of EPSP1 and EPSP2 plotted as
percentages of their control values versus time. Dashed
line indicates 100% of control value, which was determined by
averaging the traces during the preinjection period (~2 min).
Injection resulted in a greater percentage of increase in EPSP2
(open squares) than in EPSP1 (filled
squares); 20 traces per square. B2, Plot, from
experiment in B1, of depression versus time, before and
after presynaptic injection of calcium. ISI was 150 msec. Each point is
an average from 20 consecutive traces. Note that
Ca2+ injection results in a persistent decrease in
the magnitude of depression. C, Control. Similar plot as
B1, however this is a different experiment with no
Ca2+ in the electrode. M-axon was stimulated at 2 Hz
with an interval of 150 msec. No increases are found in either
amplitude, indeed both percentage amplitudes decrease.
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|
Otherwise stated, injection of Ca2+ caused
a decreased depression at the M-axon-CRN connection. An example of
this is shown in Figure 7B2, where the magnitude of
depression decreased by 9%, from a control level of 0.67 to 0.58 after
injection. The figure also illustrates that depression did not return
to control level (dashed line) at any time after the
Ca2+ injection. The magnitude of
depression decreased by 8-20% in four of the seven connections
studied and was minimally affected in the remaining three (Table 3). To
summarize, the results of the seven experiments listed in Table 3
indicate that increasing the initial probability of release with
Ca2+ injection does not result in an
increased level of depression, as predicted by the depletion model.
Rather, depression is actually decreased, a finding that is
inconsistent with a simple increase in the available pool size and
rather supports the notion that depression itself exhibits plasticity.
We also explored the possible role of heterotrimeric G-proteins in
mediating a modulation of neurotransmitter release at the M-axon to CRN
synapses. For this purpose, we injected GTPS, a nonhydrolizable
analog of GTP that irreversibly activates G-proteins (Bourne et al.,
1990; Richmond and Haydon, 1993) into the M-axon. In a limited number
of cases, GTPS produced a distinctive effect characterized by a
remarkable and selective enhancement of the first EPSP (Fig.
8A,B1), along with a
marked increase in the frequency of spontaneous EPSPs (Fig.
8B2). Note that in the example of Figure 8B1, spontaneous or asynchronous release followed the
evoked response, a phenomenon not observed in control experiments. This
combined effect was present in 3 of 10 experiments. For these three
experiments, the injection of GTPS resulted in an 83 ± 23%
growth in the amplitude of EPSP1 versus only 17 ± 14% in that of
EPSP2 (p < 0.05), and the frequency of
spontaneous EPSPs increased twofold. However, kinetics of the first and
second EPSPs were not altered after injection. The low efficacy of
GTPS injections is probably related to the distance between the
injection site and the location of the terminals as well as
difficulties in maintaining the activity of this compound during long
recording sessions; however, when the injections were effective, the
increase in the size of EPSP1 and the frequency of spontaneous EPSPs
always occurred together. Interestingly, GTPS modulation of PPD was
different to that observed for Ca2+
injections. Depression was enhanced, as in Figure 8A,
but the increased size of EPSP1 was not paralleled by a reduction of
EPSP2, which instead remained quite constant. Thus, the two presynaptic manipulations of intracellular regulatory mechanisms produced modifications of PPD inconsistent with those predicted by the depletion
hypothesis.
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Figure 8.
Presynaptic injection of GTPS selectively
increases EPSP1. A, Left and right,
Averaged paired responses (ISI = 20 msec; n = 20) obtained in control and 20 min after GTPS injection.
B1, B2, GTPS injection also modifies
spontaneous, or miniature EPSPs. B1, In another
experiment EPSP1 increases in magnitude after injection, and the
response is followed by a train of asynchronous EPSPs with slower than
normal decay times (EPSP2 not shown; traces not averaged).
B2, Recordings of synaptic noise obtained in absence of
stimulation reveal an increased frequency of spontaneous EPSPs (*)
after injection, with a prolonged decay time.
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DISCUSSION |
Our results address the questions of whether vesicle
availability is the main determinant of the release probability and
whether PPD can be modulated. One argument against depletion as the
major determinant of depression is that the size of the test response (EPSP2) was independent of the magnitude of EPSP1, and hence of the
amount of transmitter released by the first stimulus. This conclusion
is based on the assumption that the test for a correlation is sensitive
enough to detect the influence of depletion, which can be justified by
observations that this connection has ~25 release sites and a high
initial probability of release (Hackett et al., 1989; Faber et al.,
1998), such that on average >50% of the sites would be depleted by
the test stimulus. Thus, it seems likely that the presynaptic stimulus
triggers an additional process or processes that contribute to
depression. The increased synaptic latency during depression is
consistent with this concept, as is the plasticity of PPD. Similar
findings have been found at inhibitory (Korn et al., 1984) and
excitatory (Mori et al., 1994; Bellingham and Walmsley, 1999; Wu and
Borst, 1999) synapses. In contrast, depression can be attributed to
depletion at other junctions (Mori et al., 1994; Debanne et al., 1996;
Thompson et al., 1998). Thus, different systems may use different mechanisms.
Modified kinetics of release during depression
The exocytotic rate is increased transiently by a presynaptic
action potential, and this rate, (t), is the product of the probability, p, of release of a quantum, and the number
(n) of quantal release units (Stevens, 1968; Korn and Faber,
1987). Depression could be attributable to a decrease in either
parameter, and the depletion model first became popular when it was
assumed that n represented a releasable pool of vesicles
(Liley and North, 1953; Elmqvist and Quastel, 1965; Thies,
1965). More recently, a different structural correlate has been
identified for n, namely the number of active zones, each
postulated to release the contents of at most one vesicle (Korn et al.,
1982, 1994). This model would appear to preclude depletion as an
explanation of depression. However it has been suggested that at each
active zone p = pvnv, where
pv is the release probability per
vesicle, and nv is the number of
docked vesicles (Rosenmund and Stevens, 1996; Dobrunz and Stevens,
1997; Goda and Stevens, 1998). This formulation might accommodate the
depletion model if nv is small,
although several considerations suggest that
pv, or p itself, is the
target for depression (Faber et al., 1998). They include the shifts in
latency distributions and in (t).
We find that (t) is biphasic, in contrast to unimodal
waveforms described for frog (Barrett and Stevens, 1972) and lobster (Parnas and Parnas, 1987) neuromuscular junctions. Whereas those connections were analyzed under conditions of relatively low release probability, p is quite high at the M-axon to CRN
connection. When p is low, (t) might be
reduced to a single component. In addition, the synaptic delay at this
junction is significantly shorter than that reported for mammalian
synapses at the same temperature (18-20°C; see Sabatini and Regehr,
1996). While these and related issues require further study, our
finding that (t) is shifted to longer delays is again
consistent with a change in the state of the release apparatus.
Alternative mechanisms of depression
As noted above, the depression described here could be
attributable to a change in the functional state of the exocytotic machinery, a mechanism first suggested by Betz (1970). Our results also
suggest this "refractoriness" is not restricted to sites that have
undergone exocytosis, but is expressed at all release sites after a
conditioning presynaptic stimulus. That is, if the mechanism underlying
depression was operative only at sites that had contributed to the
EPSP1, there would have been a negative correlation between the
amplitudes of EPSP2 and EPSP1. Thus, we propose that the dominant
mechanism in depression is triggered by the presynaptic action
potential and occurs upstream of release itself. While the increase in
synaptic delay may reflect such a process, these results do not rule
out an additional contribution of depletion to depression.
The functional state of the secretory proteins (Calakos and
Scheller, 1996) presumably plays a major role in shaping release, including its probability and synaptic delay, and this functional state
is most likely affected by previous activity. One possible mechanism
would be a conformational change of one or more secretory proteins,
such as the putative Ca2+ sensor
synaptotagmin (Martin et al., 1995; Hsu et al., 1996; Mochida et al.,
1997; Geppert and Sudhof, 1998). Also, the calcium influx associated
with the conditioning presynaptic potential might trigger two opposing
Ca2+-dependent processes. A balance
between secretory proteins, such as synaptotagmin and rab3, a release
regulator implicated in the induction of long-term potentiation
(Castillo et al., 1997), has been proposed to mediate a gain-setting
mechanism (Geppert and Sudhof, 1998), and this balance might be
modifiable by presynaptic activity. Finally, alternative models would
involve a persistent inactivation of presynaptic
Ca2+ channels, similar to that which
contributes to posttetanic depression at the calyx of Held (Forsythe et
al., 1998). Indeed, a cotransmitter, such as adenosine (Redman and
Silinsky, 1994), might modulate channel activity.
The latency differential found during PPD may also be
attributable to a modification in the functional state of the secretory proteins. In this context, it is important to note that facilitation at
the crayfish neuromuscular junction is associated with an accelerated rate of transmitter release (Vyshedskiy and Lin, 1997). Thus, two forms
of short-term plasticity are associated with latency shifts. One
potential regulatory peptide would be SNAP-25 because cleavage of this
peptide results in more variable and longer latencies (Trudeau et al.,
1996, 1998). Alternatively, dilation of the fusion pore or
desynchronization of fusion because of reduction in the number of
fusion particles could affect release kinetics (Rahaminoff and
Fernandez, 1997; Schweizer et al., 1998).
Other possible mechanisms for the increased synaptic delay
include persistent inactivation of presynaptic
Ca2+ channels, which however, does not
alter release kinetics at the calyx of Held (Forsythe et al., 1998),
and a slowing in action potential propagation at the branch points that
give rise to the presynaptic collaterals. The latter is also unlikely:
the collaterals are ~50- to 100-µm-long, and to account for the
observed shift in latency one would have to postulate a drop in
conduction velocity to 0.6 to 1.2 m/sec for a neurite of ~25 µm in
diameter. If this delay were instead localized to the branch point
itself, it would be detected with the axonal recording (Funch et al.,
1984).
Plasticity of paired-pulse depression
We have described two examples of PPD modulated by a manipulation
that selectively alters EPSP1 or EPSP2: (1) GTPS only alters the
size of EPSP1, and (2) an increased presynaptic
Ca2+ concentration decreases depression by
preferentially enhancing EPSP2. Furthermore, the
Ca2+ effect persists for tens of minutes
after brief injection of the cation. Therefore
Ca2+ presumably initiates a cascade of
events, leading to the long-lasting augmentation of evoked exocytosis.
GTPS would be expected to also initiate a cascade. These
considerations suggest their effects mimic modifications that could be
triggered physiologically. If so, they would represent a case of
metaplasticity (Abraham and Bear, 1996), defined as a change or
transformation in the way synaptic efficacy is modified.
Metaplasticity includes long- and short-term activity-dependent
modifications (Huang et al., 1992; Wexler and Stanton, 1993; Fischer et
al., 1997). The metaplasticities triggered by
Ca2+ or GTPS differ from the
redistribution of synaptic efficacy in neocortex during repetitive
stimulation, which apparently alters the content, not the gain, of the
signal between neurons (Markram and Tsodyks, 1996). In contrast, both
Ca2+ or GTPS injections led to an
increase in total synaptic efficacy, rather than a redistribution.
Consideration of the properties of the M-cell network and the behavior
it mediates may suggest a functional correlate of this metaplasticity,
namely control of the frequency at which a fish can generate repetitive
escape responses. A single action potential in the M-cell triggers an escape response (Zottoli, 1977), mediated supraspinally by
suprathreshold excitation of CRNs, which in turn reliably activate
cranial motoneurons (for review, see Faber et al., 1989; Korn and
Faber, 1996; Zottoli and Faber, 2000). Activity-dependent depression of
M-axon output synapses helps preclude rapid initiation of two
sequential escapes that might be counterproductive. In fact, the time
constant of recovery from depression is longer than the duration of the
other predominant inhibitory process, feedback inhibition of the M-cell (Furshpan and Furukawa, 1963; 10-20 msec). Thus, altering the magnitude of spike-evoked depression can be expected to regulate the
minimal interval at which a fish could execute double startle responses.
| |
FOOTNOTES |
Received Dec. 14, 1999; revised April 24, 2000; accepted April 29, 2000.
This work was supported by the National Institutes of Health
(NS21838). We thank Carla Tyler-Polsz and Aaron Plante for
technical support, and Maurice Volaski for software development and
help in preparation of the figures.
Correspondence should be addressed to Dr. Donald S. Faber at his
present address: Department of Neuroscience, Albert Einstein College of
Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
Dr. Pereda's present address: Department of Neuroscience, Albert
Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
| |
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J. M. Sullivan
A Simple Depletion Model of the Readily Releasable Pool of Synaptic Vesicles Cannot Account for Paired-Pulse Depression
J Neurophysiol,
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[Abstract]
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H. Y. Sun, S. A Lyons, and L. E Dobrunz
Mechanisms of target-cell specific short-term plasticity at Schaffer collateral synapses onto interneurones versus pyramidal cells in juvenile rats
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Y. Wu, F. Kawasaki, and R. W. Ordway
Properties of Short-Term Synaptic Depression at Larval Neuromuscular Synapses in Wild-Type and Temperature-Sensitive Paralytic Mutants of Drosophila
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G. Fuhrmann, A. Cowan, I. Segev, M. Tsodyks, and C. Stricker
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June 1, 2004;
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H. Nakayama and Y. Oda
Common Sensory Inputs and Differential Excitability of Segmentally Homologous Reticulospinal Neurons in the Hindbrain
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G. Chen, N. C. Harata, and R. W. Tsien
From the Cover: Paired-pulse depression of unitary quantal amplitude at single hippocampal synapses
PNAS,
January 27, 2004;
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[Abstract]
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E. H. Chang, V. C. Kotak, and D. H. Sanes
Long-Term Depression of Synaptic Inhibition Is Expressed Postsynaptically in the Developing Auditory System
J Neurophysiol,
September 1, 2003;
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D. Parker
Variable Properties in a Single Class of Excitatory Spinal Synapse
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C. M. Pedroarena and C. Schwarz
Efficacy and Short-Term Plasticity at GABAergic Synapses Between Purkinje and Cerebellar Nuclei Neurons
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February 1, 2003;
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F.-C. Hsu and S. S. Smith
Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor alpha 4 Subunit Upregulation
J Neurophysiol,
January 1, 2003;
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Y. Zhao and M. Klein
Modulation of the Readily Releasable Pool of Transmitter and of Excitation-Secretion Coupling by Activity and by Serotonin at Aplysia Sensorimotor Synapses in Culture
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December 15, 2002;
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S. Kirischuk, J. D Clements, and R. Grantyn
Presynaptic and postsynaptic mechanisms underlie paired pulse depression at single GABAergic boutons in rat collicular cultures
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August 15, 2002;
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E Jankowska, U Slawinska, and I Hammar
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July 1, 2002;
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M. Takahashi, M. Narushima, and Y. Oda
In Vivo Imaging of Functional Inhibitory Networks on the Mauthner Cell of Larval Zebrafish
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May 15, 2002;
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M. Melis, R. Camarini, M. A. Ungless, and A. Bonci
Long-Lasting Potentiation of GABAergic Synapses in Dopamine Neurons after a Single In Vivo Ethanol Exposure
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March 15, 2002;
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S. Hefft, U. Kraushaar, J. R P Geiger, and P. Jonas
Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus
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February 15, 2002;
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[Abstract]
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Y. He, C. F. Zorumski, and S. Mennerick
Contribution of Presynaptic Na+ Channel Inactivation to Paired-Pulse Synaptic Depression in Cultured Hippocampal Neurons
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[Abstract]
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S. Meis, T. Munsch, and H.-C. Pape
Antioscillatory Effects of Nociceptin/Orphanin FQ in Synaptic Networks of the Rat Thalamus
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February 1, 2002;
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V. Scheuss, R. Schneggenburger, and E. Neher
Separation of Presynaptic and Postsynaptic Contributions to Depression by Covariance Analysis of Successive EPSCs at the Calyx of Held Synapse
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February 1, 2002;
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[Abstract]
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J. Kim and B. E. Alger
Random Response Fluctuations Lead to Spurious Paired-Pulse Facilitation
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December 15, 2001;
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E. Hanse and B. Gustafsson
Factors explaining heterogeneity in short-term synaptic dynamics of hippocampal glutamatergic synapses in the neonatal rat
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November 15, 2001;
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[Abstract]
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E. Hanse and B. Gustafsson
Paired-Pulse Plasticity at the Single Release Site Level: An Experimental and Computational Study
J. Neurosci.,
November 1, 2001;
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[Abstract]
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C. Rozas, H. Frank, A. J. Heynen, B. Morales, M. F. Bear, and A. Kirkwood
Developmental Inhibitory Gate Controls the Relay of Activity to the Superficial Layers of the Visual Cortex
J. Neurosci.,
September 1, 2001;
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[Abstract]
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R. D. King, M. C. Wiest, and P. R. Montague
Extracellular Calcium Depletion as a Mechanism of Short-Term Synaptic Depression
J Neurophysiol,
May 1, 2001;
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1952 - 1959.
[Abstract]
[Full Text]
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L. Marshall, D. A. Henze, H. Hirase, X. Leinekugel, G. Dragoi, and G. Buzsaki
Hippocampal Pyramidal Cell-Interneuron Spike Transmission Is Frequency Dependent and Responsible for Place Modulation of Interneuron Discharge
J. Neurosci.,
January 15, 2002;
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION
