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. 2010 Dec 1;270(1-2):101-9.
doi: 10.1016/j.heares.2010.09.003. Epub 2010 Sep 17.

Endbulb Synaptic Depression Within the Range of Presynaptic Spontaneous Firing and Its Impact on the Firing Reliability of Cochlear Nucleus Bushy Neurons

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Endbulb Synaptic Depression Within the Range of Presynaptic Spontaneous Firing and Its Impact on the Firing Reliability of Cochlear Nucleus Bushy Neurons

Yong Wang et al. Hear Res. .
Free PMC article

Abstract

The majority of auditory nerve fibers exhibit prominent spontaneous activity in the absence of sound. More than half of all auditory nerve fibers in CBA mice have spontaneous firing rates higher than 20 spikes/s, with some fibers exceeding 100 spikes/s. We tested whether and to what extent endbulb synapses are depressed by activity between 10 and 100 Hz, within the spontaneous firing rates of auditory nerve fibers. In contrast to rate-dependent depression seen at rates >100 Hz, we found that the extent of depression was essentially rate-independent (∼35%) between 10 and 100 Hz. Neither cyclothiazide nor γ-d-glutamylglycine altered the rate-independent depression, arguing against receptor desensitization and/or vesicle depletion as major contributors for the depression. When endbulb synaptic transmission was more than half-blocked with the P/Q Ca(2+) channel blocker ω-agatoxin IVA, depression during 25 and 100 Hz trains was significantly attenuated, indicating P/Q Ca(2+) channel inactivation may contribute to low frequency synaptic depression. Following conditioning with a 100 Hz Poisson train, the EPSC paired-pulse ratio was increased, suggesting a reduced release probability. This in turn should reduce subsequent depletion-based synaptic depression at higher activation rates. To probe whether this conditioning of the synapse improves the reliability of postsynaptic responses, we tested the firing reliability of bushy neurons to 200 Hz stimulation after conditioning the endbulb with a 25 Hz or 100 Hz stimulus train. Although immediately following the conditioning train, bushy cells responded to minimal suprathreshold stimulation less reliably, the firing reliability eventually settled to the same level (<50%) regardless of the presence or absence of the preconditioning. However, when multiple presynaptic fibers were activated simultaneously, the postsynaptic response reliability did not drop significantly below 90%. These results suggest that single endbulb terminals do not reliably trigger action potentials in bushy cells under "normal" operating conditions. We conclude that the endbulb synapses are chronically depressed even by low rates of spontaneous activity, and are more resistant to further depression when challenged with a higher rate of activity. However, there seems to be no beneficial effect as assessed by the firing reliability of postsynaptic neurons for transmitting information about higher rates of activity.

Figures

Figure 1
Figure 1
Synaptic depression at 10–100 Hz. A, Exemplar traces of evoked EPSC trains in a bushy neuron activated at different rates. Traces are averages of 20–40 trials for each frequency with stimulus artifacts blanked out. B, Evoked EPSCs normalized to the amplitude of the first EPSC at 10, 25, 50 and 100 Hz shock stimulation in 2 mM external [Ca2+]. Numbers in parentheses indicate cell numbers in each group. Inset: normalized EPSC at the end of 11–15 pulse trains were 0.65±0.06, 0.60±0.05, 0.67±0.03 and 0.66±0.05 of the initial EPSC amplitude for 10, 25, 50, and 100 Hz trains respectively (p>0.05).
Figure 2
Figure 2
Effects of cyclothiazide, γ-DGG and ω-agatoxin IVA on endbulb synaptic transmission. A, Left: exemplar evoked EPSCs (average of 6 trials in all traces) at 25 Hz and 100 Hz from a bushy neuron in the presence (red) and absence (black) of 50 µM CTZ. Bottom, expanded view of individual EPSCs with and without CTZ. Right: normalized EPSCs of 15 pulse trains at 25 Hz (p=0.95, n =6, paired t-test) and 100 Hz (p=0.61) with and without CTZ. B, Left: Exemplar evoked EPSCs at 25 Hz and 100 Hz from a bushy neuron in the presence (red) and absence (black) of 1 mM γ-DGG. Absolute EPSC amplitudes were reduced by ~70% in the presence of 1 mM γ-DGG. Right: normalized synaptic depressions were similar at the end of 15 pulse trains at 25 Hz and 100 Hz with (p=0.38, n=5, paired t-test) and without (p=0.22) 1 mM γ-DGG. C, Left: Exemplar evoked EPSCs before (black) and after (red) partial block of EPSCs by bath application of ~40 nM ω-agatoxin IVA. Bottom: EPSCs were 4.10±0.71 nA (before) and 0.27±0.06 nA (10 minutes after) bath application of 50 nM ω-agatoxin IVA (p=0.005, n=5, paired t-test). Right (top): normalized EPSCs of 15 pulse trains at 25 Hz (p<0.001, n =6, paired t-test) and 100 Hz (p=0.001) with (red) and without (black) partial block of the synaptic transmission. Post-drug depression was measured after EPSC amplitude was blocked by more than 50% (~71% on average). (Bottom): Attenuation of synaptic depression at the end of 25 Hz trains for individual neurons by ω-agatoxin IVA.
Figure 3
Figure 3
Reduced release probability after 100 Hz Poisson-distributed spike trains. A, Left: exemplar EPSC paired-pulse traces from control (top) and after a 100 Hz Poisson conditioning train (red). Right: paired-pulse ratios at quiescence were 0.88±0.03, 0.83±0.04 and 0.93±0.04 for 3.3, 5 and 10 ms intervals, whereas the PPRs increased to 0.97± 0.05 (p=0.061, n=8, 1-tailed t-test), 0.93±0.04 (p=0.011), and 1.04±0.04 (p=0.042) respectively for 3.3, 5 and 10 ms intervals after the 100 Hz Poisson trains. B, Left: exemplar EPSCs of 4 pulses (200 Hz) from control (top) and after a 100 Hz Poisson spike train (red). Right: normalized EPSC amplitudes for the 4 pulses at 200 Hz in control and after the Poisson conditioning trains (p<0.0001, n=8, 2-way ANOVA, * denotes paired t-test p<0.05 for individual pulses.).
Figure 4
Figure 4
Reliability of postsynaptic bushy neuron firing after conditioning trains. A, Bushy neurons were identified by their stereotypical onset response to a positive step current injection (top). With increasing auditory nerve stimulation, some bushy neurons showed a 2-step response pattern in both current-clamp (middle) and voltage-clamp (bottom). In this example neuron, the range of stimulus strength was 50–130V. In current-clamp, the step-1 action potential maximum rise slope was 115.4 mV/ms vs. 206.9 mV/ms for step-2 (middle, mean value for each step indicated by red filled squares); in voltage-clamp, the mean EPSC for step-1 was 3.2 nA vs. 4.6 nA for step-2 (bottom, Vh=−55 mV). Red traces in current- and voltage-clamp records were superimposed averages of step-1 and step-2 responses. B, Exemplar postsynaptic responses to a 200 Hz test stimulus train at step-1 or step-2 strength after conditioning the endbulb synapse with a 500 msec train at 0, 25, and 100 Hz. C, Calculated firing reliabilities to the 200 Hz test trains for the same neuron in B at step-1 and 2 stimulus strengths after conditioning at 0, 25, and 100 Hz. Legends in D applies in C. D, Group (n=6) data of the post conditioning firing reliabilities to the 200 Hz test trains. Dotted lines in step-1 curves were single exponential fits of the data. For clarity, error bars were omitted from the plot except on the last pulse in each condition.

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