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The Journal of Neuroscience, March 15, 2001, 21(6):1857-1867
Minimizing Synaptic Depression by Control of Release
Probability
Stephan
Brenowitz1, 2 and
Laurence O.
Trussell2
1 Neuroscience Training Program, University of
Wisconsin, Madison, Wisconsin 53706, and 2 Oregon Hearing
Research Center and Vollum Institute, Oregon Health Sciences
University, Portland, Oregon 97201
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ABSTRACT |
Transmission at the end-bulb synapse formed by auditory nerve
terminals onto the soma of neurons in the avian nucleus magnocellularis is characterized by high transmitter release probability and strong synaptic depression. Activation of presynaptic GABAB
receptors minimizes depression at this synapse and significantly
enhances synaptic strength during high-frequency activity. Here we
investigate synaptic mechanisms underlying this phenomenon. EPSC
amplitudes evoked by 200 Hz trains increased more than twofold when
release probability was reduced with Cd2+ or
baclofen. This effect was not exhibited by a transmitter depletion model of presynaptic depression, which predicts that EPSC amplitudes reach a common steady-state amplitude during high-frequency trains, despite alterations of initial release probability. However, an additional source of postsynaptic depression was sufficient to explain
our findings. Aniracetam, a modulator of AMPA receptors that reduces
desensitization, decreased the amount of synaptic depression during
trains, indicating that desensitization occurred during trains of
stimuli. However, this effect of aniracetam was absent when release
probability was lowered with baclofen or Cd2+. No
effect of aniracetam on the NMDA component of the EPSC was seen,
confirming a postsynaptic site of action of aniracetam. When
desensitization was reduced with aniracetam, steady-state EPSC
amplitudes during trains were found to converge over a wide range of
release probabilities, as predicted by the depletion model. Additional
evidence of AMPA receptor desensitization was provided by direct
measurement of quantal amplitudes immediately after stimulus trains.
Thus, presynaptic modulation by GABAB receptors regulates
the extent of AMPA receptor desensitization and controls synaptic
strength, thereby modulating the flow of information at an auditory synapse.
Key words:
short-term depression; AMPA receptors; desensitization; cochlear nucleus; GABAB receptors; end-bulb synapse; auditory
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INTRODUCTION |
Synaptic strength varies with the
frequency of synaptic activity as a consequence of several forms
of short- and long-term plasticity (Feng, 1940 ; Lundberg and Quilisch,
1953; DelCastillo and Katz, 1954; Kusano and Landau, 1975). Synaptic
depression is the predominant form of short-term plasticity at synapses
with high probability of transmitter release (Zucker, 1989) and has generally been attributed to depletion of a pool of readily releasable transmitter vesicles (Takeuchi, 1958; Thies, 1965; Betz, 1970; Dobrunz
and Stevens, 1997; Wu and Borst, 1999). Depression is especially
pronounced in large synapses of the auditory pathway. In the avian
nucleus magnocellularis (nMag), action potentials in the auditory nerve
evoked at low frequency (<1 Hz) generate large AMPA-mediated
EPSCs (Zhou and Parks, 1992), resulting from release of 100-200
transmitter quanta onto soma of the postsynaptic nMag neurons (Zhang
and Trussell, 1994a). However, mean firing rates of auditory nerve
fibers in vivo range from 86 to 327 Hz (Warchol and Dallos,
1990; Salvi et al., 1992). At these frequencies, synaptic responses
exhibit pronounced depression sufficient to reduce single-fiber EPSPs
below action potential threshold, eventually interrupting the relay of
timing information required for sound localization (Zhang and Trussell,
1994b; Brenowitz et al., 1998).
GABAB receptors located on end-bulb terminals of
auditory nerve fibers modulate synaptic strength in nMag in a
frequency-dependent manner. Activation of presynaptic
GABAB receptors reduces glutamate release by 85%
during low-frequency auditory nerve activity (Otis and Trussell, 1996).
However, at high rates of auditory nerve activity (up to 500 Hz),
GABAB receptor activation increases the steady-state amplitudes of synaptic responses up to fivefold relative to control, by lowering initial transmitter release and slowing onset
of depression during stimulus trains (Brenowitz et al., 1998). Because
the enhancement of synaptic strength by GABAB
receptor activation allowed suprathreshold transmission to persist
longer during high-frequency trains, this mechanism may play an
important role in allowing faithful relaying of ongoing auditory
stimuli. This finding was unexpected, because presynaptic depletion
models of depression indicate that, during high-frequency stimulation, response amplitudes reach a steady state determined by the rates of
transmitter release and vesicle recycling but not by the initial transmitter release probability (PR)
(O'Donovan and Rinzel, 1997; Tsodyks and Markram, 1997). Thus,
alterations in PR are not expected to
affect steady-state EPSC amplitudes
(EPSCSS) during high-frequency trains.
Convergence of steady-state EPSC amplitudes evoked at high frequency,
despite changes in PR, has been
confirmed in cortical (Markram and Tsodyks, 1996; Abbott et al., 1997)
and cerebellar (Kreitzer and Regehr, 2000) synapses.
Previous studies of nMag have characterized AMPA receptor
desensitization to applied glutamate or to single synaptic stimuli (Trussell et al., 1993; Raman and Trussell, 1995a; Otis et al., 1996b).
Here we describe a component of synaptic depression that persists
during repetitive stimulation of the end-bulb synapse and was
attributed to receptor desensitization. Decreasing
PR by activation of presynaptic
GABAB receptors or with
Cd2+ reduced or eliminated the
contribution of desensitization. After reduction of desensitization
with aniracetam, lowering PR no longer caused enhancement of steady-state EPSC amplitudes during
high-frequency trains. Instead, EPSCs reached the same steady-state
amplitude despite large changes in release probability. These findings
suggest that, during periods of high-frequency activity, synaptic
depression was enhanced under high but not low
PR conditions. Thus, activation of
presynaptic GABAB receptors may control synaptic
strength by regulating the extent of AMPA receptor desensitization.
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MATERIALS AND METHODS |
Physiology. Brainstem slices (300 µm) were prepared
from embryonic day 17-20 chicks (Zhang and Trussell, 1994a; Turecek
and Trussell, 2000). During dissection, storage, and recording, slices were maintained in warmed, oxygenated saline containing (in
mM): 140 NaCl, 20 glucose, 10 HEPES, 5 KCl, 3 CaCl2, and 1 MgCl2,
pH 7.35. During recordings (34-37oC),
slices were perfused at 3-5 ml/min. Neurons were viewed with a Zeiss
(Oberkochen, Germany) Axioskop and Olympus Optical (Tokyo, Japan) 60× water immersion lens using differential interference contrast optics and infrared illumination. For measurement of AMPA-mediated EPSCs, saline was supplemented with (in
µM): 100 DL-APV,
10 7-Cl-kynurenate, 10 SR-95531, and 2 strychnine. In other
experiments, NMDA-mediated EPSCs were pharmacologically isolated
by supplementing saline with (in µM): 20 GYKI-52466, 20 6,7-dinitro-7-quinoxaline-2,3-dione (DNQX), 20 SR-95531,
20 glycine, and 2 strychnine. Neurons were voltage clamped with an Axopatch 200A or 200B amplifier (Axon Instruments, Foster City, CA) at
 30 mV (for recording AMPA receptor-mediated EPSCs), +50 mV (for
recording NMDA receptor-mediated EPSCs), or 60 mV [for recording
miniature synaptic currents (mEPSCs)]. Electrode series resistance
(2-8 M ) was compensated 80-95%. Pipettes were filled with an
intracellular solution containing (in mM): 125 CH3O3SCs (Cs-methanesulfonate), 15 CsCl, 10 HEPES, 5 BAPTA, and 1 MgCl2, pH 7.25. For measurement of NMDA
responses, 2 Na2-ATP was added to the pipette
solution. Synaptic responses were obtained by positioning a stimulus
electrode (2-4 M) onto nearby myelinated fibers 20-100 µm from
the postsynaptic cell body. Individual afferent auditory nerve axons
were stimulated by 100-200 µsec, 5-50 V pulses delivered via an
isolated stimulus unit (Iso-flex; A.M.P.I., Jerusalem, Israel).
Currents were filtered at 5-10 kHz and sampled at 20 kHz. Aniracetam
stocks (0.5 M, 100×) were prepared in DMSO and added to extracellular solutions immediately before use. The final working concentration of aniracetam was 5 mM and
aniracetam-containing solutions included 1% (v/v) DMSO. For all
experiments using aniracetam, control extracellular solutions were also
supplemented with 1% DMSO. Baclofen and
Cd2+ were either added to extracellular
solutions or pressure applied with a puffer pipette (2-4 µm tip
diameter). Means are reported ± SE. Chemicals and drugs were
obtained from Sigma (St. Louis, MO), Research Biochemicals (Natick,
MA), and Tocris Cookson (Ballwin, MO).
mEPSC analysis. Frequency of spontaneous mEPSCs was enhanced
by addition of SrCl2 (2-4
mM) to extracellular solutions. Whole-cell currents were digitally sampled on a second channel using a Cygnus (Medina, OH) FLA-01 signal conditioner to increase gain 10×. mEPSCs were detected using derivative or template detection algorithms implemented in Axograph software (Axon Instruments).
Modeling synaptic depression. For simulations of synaptic
depression, the model consisted of a synapse with
N0 release sites, each of which
releases a vesicle with probability PR
after a presynaptic action potential. Immediately after release, sites
become refractory and subsequently recover with a single-exponential
time course,  D. This value is assumed to be
Ca2+-independent. Before the first
stimulus,
This notation was used by Weis et al. (1999), where
N1 refers to the releasable pool
size immediately before stimulus 1, and
N1+ refers to the releasable pool size
after stimulus 1. Thus,
After recovery during the interval between the first and second
stimuli,
where int is the interval between stimuli and
trec is the exponential time constant
for the transition of release sites from a refractory to an active
state. This model was iteratively calculated for stimulus trains of
arbitrary lengths.
Desensitization is modeled using a coefficient,  , that scales
quantal amplitudes uniformly at all release sites. The amount of
desensitization induced by each EPSC is modeled as having an exponential relationship to the quantal content:
where is the fraction of nondesensitized receptors,
mi is the quantal content of
EPSCi, and parameters A and
B define the function relating release and desensitization.
recovers with a single-exponential time course between
stimuli ( ). Before the first
stimulus,
Immediately after the first stimulus,
where m1 is the quantal content
of the first EPSC. Before the second stimulus,
After the second stimulus, receptor availability is expressed
as:
The value of was calculated iteratively throughout the
train. The amplitude of an EPSC on the ith stimulus of a
train using the desensitization model is:
where q is the quantal amplitude. To obtain values
for parameters in the model, simulations were compared with data in
Figure 4B. First, the purely presynaptic
depression model was fit to data obtained in aniracetam. This yielded
values of PR = 0.65 and
rec = 75 msec. Parameters affecting
desensitization were then determined by fitting the model to the
control data in Figure 4B, yielding values
A = 0.90, B = 1.5, and
= 100 msec.
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RESULTS |
Enhancement of synaptic strength by reducing
release probability
Stimulation of auditory nerve fibers at 200 Hz evoked large inward
currents in nMag neurons voltage clamped at a holding potential of 30
mV. During stimulus trains, the average amplitude of the first EPSC was
8.11 ± 0.62 nA and depressed to 7.1 ± 2.2% of this value
during trains of 10 stimuli (n = 6) (Fig.
1A,B;
see Fig. 4B). As shown previously (Brenowitz et al.,
1998), activation of presynaptic GABAB receptors
by bath application of baclofen (50 µM) reduced
initial response amplitudes to 16 ± 3% of control (n = 6). However, depression during 200 Hz trains was
minimal in baclofen, so that after two to three stimuli, absolute EPSC amplitudes in baclofen were enhanced 215 ± 35% relative to
controls (n = 6) (Fig.
1Aii,C, filled circles).
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Figure 1.
Enhancement of synaptic strength by lowering
release probability. Ai, Trains of 10 EPSCs were evoked
at 200 Hz under control conditions (bottom trace) or in
the presence of 50 µM baclofen (top
trace). The first peak in baclofen was reduced to 19.3% of
control. Vm = 30 mV. Averages of
5-10 trials are shown. Stimulus artifacts have been removed.
Aii, EPSCs 8-10 have been enlarged to illustrate the
increase in EPSC amplitudes when initial release probability was
reduced with baclofen (control, black trace; baclofen,
gray trace). Bi, Same as in
A, but in the presence of Cd2+ (20 µM) (top trace). Peak of EPSC1
in Cd2+ was reduced to 20.1% of control.
Bii, EPSCs 8-10 have been enlarged to illustrate
enhancement of EPSCSS in the presence of
Cd2+ (control, black trace;
Cd2+, gray trace). C,
Filled circles show amplitude ratio of EPSCs in baclofen
to controls for each stimulus. As the control EPSCs depress during the
train, this value increases. Average enhancement of EPSCs for stimuli
8-10 in this cell was 223%. Open circles show ratios
of EPSCs in Cd2+ relative to controls. Average
steady-state enhancement of EPSCs in this cell was 186%. Data in
A-C are from two different neurons. D,
Bar graph comparing results for Cd2+
(n = 6) and baclofen (n = 6).
Black bars show ratios of EPSC1 amplitude in
50 µM baclofen or 20 µM
Cd2+ relative to control (EPSC1, BAC (or
Cd)/EPSC1, CON). Gray bars
show ratios of steady-state EPSC amplitude (average of EPSCs 8-10 of
200 Hz trains) in baclofen or Cd2+ relative to
control (EPSCSS, BAC (or Cd)/EPSCSS,
CON).
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Because activation of presynaptic GABAB receptors
with baclofen reduces Ca2+ currents (Bean,
1989; Dittman and Regehr, 1996; Wu and Saggau, 1997), we examined
whether block of Ca2+ currents with
Cd2+ could produce a similar enhancement
of EPSCSS (average of EPSCs 8-10). Bath
application of 20 µM Cd2+
reduced amplitudes of single EPSCs to 14 ± 2% of controls,
statistically indistinguishable from the effect of 50 µM
baclofen (Fig. 1B,D, black
bars). Stimulus trains delivered at 200 Hz in the presence of 20 µM Cd2+ caused
enhancement of EPSCs to 180 ± 10% relative to control (n = 6) (Fig. 1B-D, gray
bars). With equivalent levels of block of the first EPSC, the
enhancement of EPSCs by Cd2+ and baclofen
during 200 Hz trains was similar, suggesting that effects of baclofen
result solely from a reduction of the initial probability of
transmitter release (Kreitzer and Regehr, 2000). When trains of 30-50
stimuli were delivered (n = 6; data not shown), EPSC
enhancement persisted under conditions of lowered
PR, indicating that this enhancement
is not a transient phenomenon attributable to a failure of EPSC
amplitudes to reach steady-state.
Synaptic strength is maximized at intermediate values of initial
release probability
To explore further the effect of changing initial
PR on EPSCSS, we
delivered 200 Hz stimulus trains while varying
PR with Cd2+. A high concentration of
Cd2+ (100 µM),
sufficient to block transmission in nMag completely, was applied by
bath perfusion or local pressure ejection near the cell.
Cd2+ levels were varied by gradual
reperfusion of control bath solution (containing 0 µM Cd2+) or by
repositioning the puffer pipette various distances from the cell (Fig.
2Ai). Trains of EPSCs
were recorded at 15 sec intervals in concentrations of
Cd2+ that ranged from 0 to 100 µM, producing a wide range of amplitudes of the
first EPSC (EPSC1) in each train (Fig.
2Ai). Enhancement of EPSCSS was
seen to accompany reduction of PR
(Fig. 2Aii). Figure 2B illustrates
the relationship between EPSCSS and
PR. Figure 2, A and
B, shows an example in which maximal enhancement of
EPSCSS was 411-422% when
EPSC1 was reduced to between 7 and 12% of its control value. Further reductions of
PR caused EPSCSS
to decline and approach zero, as expected with nearly complete block of
Ca2+ channels. Similar observations were
made in 11 neurons. Data were pooled from six neurons in which a large
number of responses (25-135) were recorded (Fig. 2C). In
this group, average enhancement of EPSCSS was
232% when EPSC1 was blocked with
Cd2+ to between 1 and 2 nA. These
experiments demonstrate that EPSCSS amplitudes
were enhanced under conditions of reduced
PR.
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Figure 2.
Relationship between EPSCSS
and PR. Ai, Trains (200 Hz)
of 10 stimuli were recorded in levels of Cd2+ranging
from 0 to 100 µM. The first EPSC in each train is shown.
Aii, Superimposed traces in high Cd2+
(gray trace) and in 0 Cd2+
(black trace). B, EPSCSS
(averages of EPSCs 8-10) are plotted versus amplitude of the first
EPSC for each train. C, Pooled results from six neurons.
Data from each neuron were grouped in bins associated with
EPSC1 values from 0-1, 1-2 nA, etc. Means and SEs were
calculated for each bin. A linear fit to the data
points (excluding the leftmost point associated
with the smallest value of EPSC1) indicated a
significant negative correlation between EPSC1 and
EPSCSS (r2 = 0.968;
p < 0.0001).
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Because modulation of PR in
vivo may occur via activation of presynaptic
GABAB receptors, we used the same experimental
approach to record EPSC trains in the presence of baclofen
concentrations ranging from 0 to 100 µM (Fig.
3). At 100 µM,
the effect of baclofen is expected to be saturating, given an
IC50 of 9 µM for baclofen of inhibition of the initial EPSC (data not shown). As noted earlier, baclofen enhanced EPSCSS by more than twofold
during 200 Hz trains, but unlike Cd2+, no
suppression of EPSCSS was obtained even at the
highest concentrations of baclofen. Figure 3, A and
B, shows data from a neuron in which EPSCSS was enhanced 3.6-fold when the first EPSC
in the train was reduced to 6.8% of its control value. As release
during the first stimulus of the train was progressively blocked with
saturating baclofen, the value of EPSCSS
increased and reached a plateau (Fig. 3B). Similar
observations were made in 13 neurons. Data were pooled from six neurons
in which numerous responses (43-96) were obtained (Fig.
3C). In this group, EPSCSS was
enhanced on average by 218% when EPSC1 was
reduced to less than 3 nA with baclofen. Thus, at high stimulus
rates, full activation of GABAB receptors appears
to maximize synaptic strength.
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Figure 3.
Effect of baclofen on EPSCSS.
Ai, Trains (200 Hz) were delivered in baclofen
concentrations ranging from 0 to 100 µM. The first EPSC
of the train is shown. Aii, Responses in 0 and 100 µM baclofen are shown. After the second stimulus of the
train, EPSCs in baclofen are larger than controls. B,
EPSCSS is plotted against EPSC1 of each train.
As PR is lowered with baclofen, steady-state
EPSCs increase in size, reaching a plateau as saturating levels of
baclofen are reached. In this cell, enhancement
of EPSCSS relative to control was 361% when
EPSC1 was reduced with baclofen to between 5.1 and 8.1% of
its control value. C, Pooled data from six neurons. Data
were binned as in Figure 2C. A linear fit to the
eight rightmost data points was highly significant
(r2 = 0.903;
p < 0.001).
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Contribution of AMPA receptor desensitization to depression during
high-frequency trains
One hypothesis to account for the changes we observed
in EPSCSS that accompany changes in
PR is that AMPA receptors undergo desensitization during stimulus trains delivered only when
PR is high. To investigate the
contribution of AMPA receptor desensitization to synaptic depression,
we evoked trains of stimuli at 200 Hz in the presence of 5 mM aniracetam, a drug that reduces AMPA receptor desensitization (Vyklicky et al., 1991, Raman and Trussell, 1995b; Partin et al., 1996). Although desensitization will occur to high concentrations of glutamate in the presence of aniracetam, its onset is
slowed dramatically in nMag, and should be minimal with stimulus
intervals of 5 msec (Raman and Trussell, 1995b; J. Lawrence and L. O. Trussell, unpublished observations). Effects of aniracetam on
single EPSCs are shown in Fig.
4Ai. Control EPSC
amplitudes were 7.60 ± 0.65 versus 10.52 ± 0.97 in 5 mM aniracetam (an increase of 37.2 ± 4.3%;
n = 16). Half-decay times were 0.80 ± 0.04 for
controls versus 2.33 ± 0.12 msec in aniracetam (an increase of
197 ± 16%; n = 16) (Fig. 4Ai).
Effects of aniracetam on peak amplitude and decay rate of AMPA-mediated
EPSCs are attributed to modulation of receptor kinetics, which include
an increase in the open time of the channel and a slowing of entry into
desensitized states (Raman and Trussell, 1995b; Partin et al.,
1996).
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Figure 4.
Effect of aniracetam on synaptic depression.
Ai, A single EPSC in 5 mM aniracetam
(gray trace). Control peak (black
trace) is indicated with an arrow. In this cell,
aniracetam increased the peak amplitude by 60% (from 6.19 to 10.24
nA). Aii, A 200 Hz train in control (black
trace) and aniracetam (gray trace) is
shown. Traces have been normalized to the amplitude of the first peak
in each train. Averages of five traces are shown. Bi,
Normalized peak amplitudes during 200 Hz stimulus trains (control,
black circles; aniracetam, gray circles).
Data from 13 cells. Depression is significantly reduced by aniracetam
for stimuli 2-10 of trains (p < 0.01;
paired t test). Bii, Relative enhancement
of EPSC amplitudes by aniracetam throughout the train, calculated as
100% · (EPSCANI EPSCCON)/EPSCCON. C,
Effect of aniracetam on synaptic depression in the continuous presence
of 20 µM Cd2+. Ci, EPSC
trains at 200 Hz in 20 µM Cd2+
(black trace) and 20 µM
Cd2+ plus 5 mM aniracetam
(gray trace). In this example, aniracetam
increased the peak of the first EPSC by 55.8% (from 0.84 to 1.30 nA).
Cii, Responses during trains in the presence of
Cd2+ (black circles) and
Cd2+ plus aniracetam (gray
circles) were normalized to the first response amplitude and
plotted versus stimulus number. No effect of aniracetam on synaptic
depression was seen when PR was lowered with
20 µM Cd2+ (n = 12).
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To determine the effect of aniracetam on synaptic depression during 200 Hz stimulation, we normalized peaks to the amplitude of the first EPSC
in each train (Fig. 4Aii). By comparing relative amounts of depression after normalization, effects of aniracetam on
desensitization during stimulus trains can be explored. Because EPSCs
recorded at high frequency in aniracetam exhibited summation, peaks
were measured from a baseline obtained by extrapolating the decay of
the preceding EPSC using a single-exponential function. Synaptic
depression during 200 Hz trains was reduced by aniracetam (Fig.
4Bi). After normalization of
EPSC1, EPSCs 2-10 were significantly larger in
aniracetam (p < 0.002 for each stimulus; paired
t test; n = 13). Enhancement by aniracetam
of EPSCs 2-10 of the train was calculated after normalization of
EPSC1 as 100% · (EPSCANI EPSCCON)/EPSCCON (Fig.
4Bii). Maximal enhancement of the EPSC by aniracetam
was seen during the second stimulus (131% larger than control) and
declined slightly during trains (110% enhancement of the
10th stimulus). Thus, over 50% of
synaptic AMPA receptors remained desensitized throughout 200 Hz trains
of 10 stimuli.
In contrast, when release was blocked by ~85% with 20 µM Cd2+ (Fig.
4Ci,Cii) or 50 µM
baclofen (data not shown), no effect of aniracetam on normalized EPSC
amplitudes was observed (Fig. 4Cii). This suggests that
desensitization contributes to synaptic depression under control
release conditions but not when PR is
reduced by baclofen or Cd2+. Notably, the
approximately twofold enhancement of EPSCs during 200 Hz trains by
relief of desensitization (Fig. 4Bii) was similar to
the enhancement of EPSCs observed when release was blocked with
Cd2+ or baclofen (Figs.
1D, 2C, 3B). This similarity
suggests that relief of desensitization may contribute to the
enhancement of EPSCSS observed when
PR was lowered with
Cd2+or baclofen.
Convergence of EPSC amplitudes with relief of desensitization
Because desensitization caused a decrease in
EPSCSS under high-release conditions, we
predicted that EPSCSS would remain constant over
a wide range of initial release probabilities if desensitization was
reduced by aniracetam. To test this hypothesis, experiments similar to
those presented in Figure 2 were conducted in the continuous presence of 5 mM aniracetam. Trains were recorded at 15 sec
intervals while PR was varied by bath
application and subsequent washout of 100 µM
Cd2+ (Fig.
5Ai). Under these conditions,
EPSCSS amplitudes converged on the same value
during 200 Hz trains despite large changes in PR (Fig.
5Aii,B). Figure 5B indicates that,
whereas initial EPSC amplitudes varied fourfold (from 2 to 8 nA),
steady-state EPSCs remained constant at ~1.5 nA. Similar results were
obtained in eight neurons. Figure 5C (filled
circles) shows pooled data from seven neurons from which a large
number of responses (21-60) were recorded, as described in Figure 2.
The slope of a linear regression of the eight rightmost data
points in Figure 5C (filled circles) was not significantly different from zero (slope of 0.029;
p = 0.198). For comparison, the control data from
Figure 2C were scaled up by 37% to account for the effect
of aniracetam on the initial EPSC amplitude and were plotted in Figure
5C as open circles.
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Figure 5.
Convergence of EPSCSS in the presence
of aniracetam A, In the continuous presence of 5 mM aniracetam, 200 Hz trains of 10 stimuli were delivered
in various concentrations of Cd2+ ranging from 0 to
100 µM. Ai, The first EPSC of each train
is shown. Aii, Superimposed traces in high
Cd2+ (gray trace) and low
Cd2+ (black trace) are shown.
B, EPSCSS is plotted versus
EPSC1 for each train. C, Data from seven
cells in aniracetam (filled circles). As in
Figure 2, data from each neuron were grouped in bins associated with
EPSC1 values from 0-1, 1-2 nA, etc. Means and SEs were
calculated for each bin. The slope of a linear fit to the data
points (excluding the 2 leftmost points
associated with EPSC1 values from 0 to 2 nA) was not
significantly different from 0 (r2 = 0.26;
p = 0.20). Control data from Figure
2C have been scaled up by a factor of 1.37 to account
for the effect of aniracetam on the amplitude of a single EPSC (see
Fig. 4A) and are shown for comparison
(open circles).
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The experiments presented in Figure 5 demonstrate that, in the presence
of aniracetam, EPSCs approach the same amplitude during trains despite
large variations in the transmitter release probability, in agreement
with predictions of purely presynaptic depletion models of synaptic
depression (see below). These data indicate that the progressive
decline in EPSCSS seen as
PR increased (Figs. 2C,
3B) results from AMPA receptor desensitization under
high-release conditions. Thus, relief of desensitization can account
for the enhancement of EPSCSS that results from
lowering PR by
GABAB receptor activation or
Cd2+ application.
Alternative actions of aniracetam
Control experiments were performed to determine whether
presynaptic effects of aniracetam might have influenced the above conclusions, although previous studies found no effect of aniracetam on
quantal content of EPSCs (Vyklicky et al., 1991). Effects of aniracetam
on transmitter release were expected to alter paired-pulse ratios
(EPSC2/EPSC1) of NMDA
responses, as reported previously for cyclothiazide (Bellingham and
Walmsley, 1999). NMDA-mediated EPSCs were recorded at +50 mV in
the presence of AMPA receptor blockers. Paired stimuli were delivered
at 20 msec intervals under control conditions (Fig.
6Ai) or in the presence
of 5 mM aniracetam (Fig. 6Aii).
Paired-pulse ratios for the NMDA component of the EPSC were compared in
nine neurons (Fig. 6B). For controls, average paired-pulse ratio was 0.27 ± 0.01; in the presence of 5 mM aniracetam, the average value was 0.26 ± 0.01. These values were not significantly different
(p = 0.480; paired t test).
Paired-pulse ratios of AMPA-mediated EPSCs were significantly larger
(paired-pulse ratio of 0.49 ± 0.02; p < 0.01;
paired t test) (Fig. 6C). Based on the higher affinity of the NMDA receptor for glutamate, we attribute this finding
to greater occupancy of NMDA receptors at the onset of the second
stimulus. Receptor desensitization may also contribute to paired-pulse
depression (PPD) of NMDA responses. Additional evidence for a purely
postsynaptic site of action for aniracetam is indicated by the absence
of an effect of aniracetam on the relative amplitudes of AMPA-mediated
EPSCs during stimulus trains under low
PR conditions (Fig.
4Cii).
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Figure 6.
NMDA component of EPSC is not affected by
aniracetam. A, Pairs of EPSCs at 20 msec intervals were
recorded at +50 mV in GYKI-52466 and DNQX under control conditions
(Ai) and in 5 mM aniracetam
(Aii). Average of five traces. Peak 2 (bottom
traces) in Ai and Aii was
obtained by subtraction of the averaged single EPSC (data not shown).
B, Paired-pulse ratios
(EPSC2/EPSC1) for responses in
control solutions and in 5 mM aniracetam
(n = 9). C, Average values of
EPSC2/EPSC1 for NMDA component of EPSC
(control and aniracetam) and AMPA component (control;
n = 9).
|
|
As transmitter release declines during high-frequency trains, it is
possible that postsynaptic sites are exposed to progressively lower
concentrations of glutamate. If this were true, then EPSC enhancement
by aniracetam during trains might simply be an outcome of the drug
increasing the affinity of AMPA receptors, apart from preventing
desensitization. We determined whether the effectiveness of aniracetam
changed with quantal content by comparing the effects of the
drug on mEPSCs and evoked EPSCs. If receptors were farther from
saturation during mEPSCs than during EPSCs, then the effects of
aniracetam on peak current should be greatest for mEPSCs. However, this
was not the case. In a group of six neurons, mEPSCs enhancement by
aniracetam was 14.5 ± 5.2%, slightly less than enhancement of
evoked EPSCs, which was 25.7 ± 6.9%. These values were not significantly different (p = 0.12; paired
t test). Thus, effects of aniracetam on affinity of AMPA
receptors for glutamate cannot account for the enhancement of EPSC
amplitudes during trains.
Quantal amplitudes are depressed after single stimuli and
after trains
It has been shown previously in nMag that desensitization of AMPA
receptors causes a decrease in the size of the mEPSC immediately after
a single evoked EPSC (Otis et al., 1996b). Others, however, have not
observed a decrease in postsynaptic responsiveness to transmitter after
a single EPSC (Silver et al., 1998; Bellingham and Walmsley,
1999) or during trains (Silver et al., 1998). We therefore
reexamined this effect, in particular contrasting changes in quantal
size with single or multiple conditioning EPSCs. After EPSCs evoked in
the presence of Sr2+ (2-4
mM), an elevated frequency of asynchronous quantal release is observed in nMag (Otis et al., 1996b) and other preparations (Rahamimoff and Yaari, 1973; Xu-Friedman and Regehr,
1999). Therefore, we recorded single EPSCs and trains of five
EPSCs at 200 Hz, in the presence of Sr2+.
Amplitude and latency of quantal events were measured after the
stimulus (Fig.
7Ai,Bi). Between 50 and 100 consecutive traces were recorded to obtain sufficient quantal
events for analysis (Fig. 7Aii,Bii). Quantal
amplitudes were sorted by latency and binned into groups of 30 successive events. For each bin, mean amplitude was plotted against
mean latency from the peak of the preceding EPSC (Fig.
7Aiii,Biii). After one and five stimuli, quantal
amplitudes were depressed by 36.5 ± 3.9 (n = 5)
and 36.3 ± 3.5% (n = 5), respectively.
Amplitudes recovered with a single-exponential time constant of
21.1 ± 2.9 and 10.6 ± 2.0 msec, respectively. The overall
extent of depression after one or five stimuli was not statistically
different; however, the time course of recovery was significantly
faster after five stimuli (p < 0.01;
t test). In these experiments, a maximum train length of
five stimuli was used because longer trains resulted in a high
frequency of asynchronous quantal release whose superposition prevented
resolution of individual events. These results are in agreement with
the results obtained using aniracetam (Fig. 4), indicating the
persistent desensitization of AMPA receptors during high-frequency
stimulus trains.
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|
Figure 7.
Depression of quantal size during stimulus trains.
Ai, Averaged EPSC recorded in 3 mM
Sr2+. Aii, Twenty superimposed traces
after a single stimulus. Asynchronously released quanta are visible
arising from the decay of the preceding EPSC. Dotted
line indicates zero-current baseline. Aiii,
Means and SE of amplitude and latency for quantal events binned in
groups of 30. For this synapse, the amplitude of the first bin was
depressed by 49% relative to the steady-state amplitude at longer
latencies. A single-exponential fit to the data gave a recovery time
course of 27 msec. Bi, Averaged traces from a train of
five stimuli at 200 Hz in 3 mM Sr2+.
Bii, Twenty-five superimposed traces after the fifth
EPSC of the train shown in Bi. Biii, Mean
amplitude and latency for quantal events binned in groups of 30. In
this synapse, the amplitude of the first bin was depressed by 38%
relative to steady-state amplitude at longer latencies. Recovery time
course of quantal amplitudes was 11 msec.
|
|
Modeling depression and desensitization
Simulations were performed to determine whether the experimental
results presented in Figures 2 and 5 could be explained by incorporating receptor desensitization into a depletion model of
synaptic depression (Fig. 8). The model
consists of a synapse with N0 release
sites that release transmitter with probability PR after a presynaptic action
potential. Sites becomes refractory immediately after release and
subsequently recover with a single-exponential time course (see
Materials and Methods). Although alternative presynaptic models have
been developed (Wu and Borst, 1999; Kraushaar and Jonas, 2000; Matveev
and Wang, 2000), a depletion model was used here because it accurately
reproduced our synaptic data obtained in the presence of aniracetam.
Postsynaptic desensitization was modeled by introducing a scaling
factor in the model that reduced quantal size uniformly at all sites
and was dependent on the amount of release. Desensitization had an
exponential relationship to the amount of release and recovered with a
single-exponential time course. Parameters of the model were determined
by fitting the simulated results to the data shown in Figure
4B. The presynaptic component of the model is similar
in many respects to previously published models (O'Donovan and Rinzel,
1997, Dittman and Regehr, 1998, Weis et al., 1999; Lu and Trussell,
2000).
View larger version (15K):
[in this window]
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|
Figure 8.
Depletion and desensitization model of synaptic
depression. A, Simulations based on a presynaptic
depletion model that does not include receptor desensitization. Trains
of 10 stimuli at 200 Hz with PR values
ranging from 0.02 to 0.75. Smaller responses to stimulus
#1 correspond to lower PR values.
Time constant of recovery from depression was 100 msec. EPSCs reached
similar steady-state values when PR ranged
from 0.15 to 0.75. Inset on right shows
the 10th response on an expanded vertical scale. Note that data
points are superimposed from trains with
PR of 0.15 to 0.75. Y values
(normalized to EPSC1) for these four data
points ranged from 0.075 to 0.079. B,
Desensitization was included in the model as described in Materials and
Methods. PR was varied as in
A. Steady-state EPSCs were maximal at
PR = 0.15. Inset shows
10th response on an expanded vertical scale. C,
EPSCSS is plotted versus EPSC1. Results of the
presynaptic model are shown by filled circles; results
of simulations incorporating postsynaptic desensitization are shown
with open circles.
|
|
Figure 8A shows results of simulations of 200 Hz
stimulus trains using a presynaptic depletion model in which
PR ranged from 0.02 to 0.75. At steady
state, each presynaptic action potential evoked release from ~8% of
the total population of release sites when initial release probability
is greater than 0.15 (Fig. 8A,C). As
PR decreased below 0.15, the amount of
release was no longer limited by interstimulus recovery but instead was
limited by extremely low fusion probability. As shown in Figure
8C (filled circles), a purely presynaptic
model of depression predicted that steady-state EPSC amplitudes evoked
at high frequency (i.e., the stimulus interval is much faster than the
time constant of recovery from depression) converge on the same value
despite large changes in initial release probability. However, when the
model incorporated postsynaptic receptor desensitization (see Materials
and Methods), we observed a progressive reduction of
EPSCSS as PR
increased (Fig. 8B,C, open
circles), in agreement with our experimental results (Figs. 2B,C, 3, 5C). The
ability of this model to reproduce these key features of our
experimental results strongly suggests that desensitization can account
for the decline in EPSCSS with high
PR.
| |
DISCUSSION |
This work demonstrates that desensitization of AMPA receptors
contributes strongly to synaptic depression during high-frequency activity at avian end-bulb synapses in the auditory brainstem. Desensitization was dependent on the amount of transmitter release at
the onset of a stimulus train. With high initial transmitter release
probability, approximately half of the postsynaptic AMPA receptors were
desensitized at the end of a 50 msec, 200 Hz stimulus train. However,
desensitization decreased as PR was
reduced, thereby enhancing amplitudes of steady-state EPSCs during
stimulus trains. Thus, relief of AMPA receptor desensitization can
account for the enhancement of steady-state EPSC amplitudes that
accompany reduction of release probability with baclofen or
Cd2+.
During stimulus trains, transmitter release approaches a steady-state
that occurs when vesicle depletion after each stimulus is equal to
recovery between stimuli. Depression models that consider only
transmitter depletion predict that, during high-frequency stimulation,
the steady-state EPSC amplitude is independent of PR (except for extremely low
PR) because of an inverse relationship between PR and the size of the
steady-state vesicle pool. With high
PR, steady-state pool size is small
and a large fraction of the pool is released with each stimulus, but
with low PR, the steady-state pool
size is large and only a small proportion of available release sites
undergo exocytosis with each stimulus. This ideal relationship is an
approximation that holds at stimulus frequencies for which the interval
between stimuli is much shorter than the time constant of recovery from
depression. In our experiments, block of desensitization resulted in
convergence of EPSC amplitudes during high-frequency trains, indicating
that release approaches a steady-state during the stimulus trains. If
Ca2+-dependent processes cause
acceleration of recovery from synaptic depression, as described at
other synapses (Dittman and Regehr, 1998; Stevens and Wesseling, 1998;
Wang and Kaczmarek, 1998; Wang and Zucker, 1998) (but see Weis
et al., 1999; Wu and Borst, 1999), EPSCSS should
have declined with reductions in presynaptic
Ca2+ influx, i.e., as
EPSC1 was lowered. However,
EPSCSS was independent of
EPSC1 over a wide range of release probabilities
after block of postsynaptic depression. This suggests that, over the
range of Ca2+ influx associated with this
range of release probabilities,
Ca2+-dependent processes act at a constant
level, and perhaps under our experimental conditions
Ca2+-dependent recovery processes are
saturated by Ca2+ influx during trains of stimuli.
Changes in release probability have presynaptic and postsynaptic
effects on transmission at the end-bulb synapse. Under low-release conditions, release of relatively few vesicles results in a rapidly decaying glutamate transient at a receptor cluster opposite an active
release site. With higher release probability, transmitter will be
released synchronously from many sites, generating a slower phase of
decay of the glutamate transient in the synaptic cleft (Otis et al.,
1996a). We observed a current plateau between EPSCs during 200 Hz
trains, which has been attributed to accumulation of glutamate in the
synaptic cleft (Turecek and Trussell, 2000). Modeling studies have
suggested that the glutamate concentration in the synaptic cleft will
remain above 10 µM for tens of milliseconds after release
under high PR conditions. AMPA
receptors undergo desensitization in the presence of micromolar
concentrations of agonist insufficient to cause channel openings (Raman
and Trussell, 1992). Experiments in which glutamate was applied to
membrane patches excised from nMag neurons indicate that 10 µM glutamate will induce ~70% steady-state
desensitization of AMPA receptors (Raman and Trussell, 1992). Thus, low
concentrations of glutamate that persist in the synaptic cleft during
trains may contribute to desensitization that we observed during
periods of high-frequency synaptic activation.
In addition, brief exposure of AMPA receptors to high concentrations of
agonists can induce a form of desensitization that accompanies channel
opening. One millisecond application of 1 mM glutamate to
membrane patches at room temperature caused 50% desensitization of
AMPA receptors, which subsequently recovered with a 16 msec exponential
time constant (Raman and Trussell, 1995a). During trains, the relative
contribution to desensitization of prolonged exposure to low glutamate
concentrations and brief exposure to high concentrations is not known.
At room temperature, a single evoked EPSC desensitized 35-40% of
synaptic AMPA receptors, recovering with a time constant of 68 msec
(Otis et al., 1996b). At near-physiological temperatures, we observed a
greater extent of desensitization, which recovered with a time constant
of 21 msec. Faster recovery may be attributable to more rapid clearance
of glutamate from the synaptic cleft and faster gating kinetics of AMPA
receptors. Desensitization of AMPA receptors during synaptic activation
was also shown to be dependent on the total amount of transmitter
release (Trussell et al., 1993). PPD of EPSCs in low
Ca2+ showed little sensitivity to
cyclothiazide, but in higher Ca2+
concentrations, relief of PPD by cyclothiazide was observed. Moreover,
synaptic depression during 200 Hz trains was reduced by cyclothiazide
(Zhang and Trussell, 1994a) and by a glutamate scavenging enzyme
(Turecek and Trussell, 2000), indicating persistent AMPA receptor
desensitization during periods of repetitive stimulation. These results
are consistent with our observation that desensitization persists
during stimulus trains delivered under conditions of high
PR but not under conditions of low
PR.
Because we demonstrate that desensitization depends on the amount of
evoked release during trains, it is predicted that presynaptic depression will allow receptors to recover from desensitization during
periods of prolonged activity. During 200 Hz stimulation, <10% of
release sites undergo exocytosis after each stimulus so that, on
average, several stimuli will elapse between successive events of
vesicle fusion at a particular release site. However, we saw little
decline in the extent of receptor desensitization during 50 msec trains
(Fig. 4Bii), as estimated by the enhancing effect of
aniracetam. The persistence of AMPA receptor desensitization despite
>90% reduction in transmitter release may be explained by
accumulation and slow clearance of transmitter in the synaptic cleft.
Although a large reduction of PR by
Cd2+ ultimately caused a decline in
EPSCSS from its plateau value (Fig.
2C), reduction of PR by
GABAB receptor activation using a saturating
concentration of agonist always raised EPSCSS.
Based on a 3rd or 4th power relationship between calcium influx and
transmitter release (Dodge and Rahamimoff, 1967; Augustine and
Charlton, 1986; Borst and Sakmann, 1996), an 85% reduction of a single
EPSC by saturating levels of baclofen indicates that maximal activation
of GABAB receptors reduced presynaptic calcium
influx by 38-47%. This observation suggests precise regulation of the
coupling between GABAB receptors and
Ca2+ channels involved in transmitter
release, so that release is never actually inhibited during intense
activity. Sites of such regulation could include the number of
GABAB receptors, levels of expression of
G-proteins, extent of modulation of particular Ca2+ channels subtypes, and the degree of
coupling of different Ca2+ channel types
to release.
Synaptic depression has been proposed to play an important role in
promoting network stability in the cerebral cortex (Galarreta and
Hestrin, 1998) and has been described as a mechanism that enables
neurons to maintain responsiveness to the firing patterns of a large
number of afferents (Abbott et al., 1997). However, at end-bulb
synapses in the cochlear nucleus, a role for synaptic depression is
less clear. Bushy cells serve as relays in a timing pathway enabling
sound localization (Carr and Konishi, 1990; Overholt et al., 1992). In
the avian brainstem, GABAergic neurons from the superior olivary
nucleus are activated by sounds and project to nMag, in which they may
activate GABAB receptors on auditory nerve
terminals (Lachica et al., 1994; Monsivais et al., 2000). The
feed-forward nature of this pathway should cause GABA release by
superior olivary neurons to increase approximately in parallel with
end-bulb synaptic activity. Because desensitization is likely to result
from in vivo firing rates of the auditory nerve, activation of presynaptic GABAB receptors could serve to
minimize synaptic depression by relieving desensitization, thereby
allowing suprathreshold transmission to persist at higher rates of
synaptic activity. Such an enhancement of gain may help widen the
dynamic range of sensory signaling.
| |
FOOTNOTES |
Received Oct. 18, 2000; revised Dec. 7, 2000; accepted Dec. 22, 2000.
This work was supported by National Institutes of Health Grants NS28901
(L.O.T.) and GM07507 (S.B.). We thank Drs. V. Alvarez, J. Diamond, R. Fettiplace, T. Lu, I. Raman, and R. Turecek for helpful discussions and
comments on this manuscript.
Correspondence should be addressed to Stephan Brenowitz, Auditory
Neuroscience L-335A, Oregon Health Sciences University, 3181 SW Sam
Jackson Park Road, Portland, OR 97201. E-mail: brenowit{at}ohsu.edu.
| |
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V. Scheuss, R. Schneggenburger, and E. Neher
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S. Brenowitz and L. O. Trussell
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S. Oleskevich and B. Walmsley
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TOP
ABSTRACT
INTRODUCTION
