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. 2006 Dec;7(4):412-24.
doi: 10.1007/s10162-006-0052-9. Epub 2006 Oct 26.

Temporal Coding by Cochlear Nucleus Bushy Cells in DBA/2J Mice With Early Onset Hearing Loss

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Free PMC article

Temporal Coding by Cochlear Nucleus Bushy Cells in DBA/2J Mice With Early Onset Hearing Loss

Yong Wang et al. J Assoc Res Otolaryngol. .
Free PMC article

Abstract

The bushy cells of the anterior ventral cochlear nucleus (AVCN) preserve or improve the temporal coding of sound information arriving from auditory nerve fibers (ANF). The critical cellular mechanisms entailed in this process include the specialized nerve terminals, the endbulbs of Held, and the membrane conductance configuration of the bushy cell. In one strain of mice (DBA/2J), an early-onset hearing loss can cause a reduction in neurotransmitter release probability, and a smaller and slower spontaneous miniature excitatory postsynaptic current (EPSC) at the endbulb synapse. In the present study, by using a brain slice preparation, we tested the hypothesis that these changes in synaptic transmission would degrade the transmission of timing information from the ANF to the AVCN bushy neuron. We show that the electrical excitability of bushy cells in hearing-impaired old DBA mice was different from that in young, normal-hearing DBA mice. We found an increase in the action potential (AP) firing threshold with current injection; a larger AP afterhyperpolarization; and an increase in the number of spikes produced by large depolarizing currents. We also tested the temporal precision of bushy cell responses to high-frequency stimulation of the ANF. The standard deviation of spikes (spike jitter) produced by ANF-evoked excitatory postsynaptic potentials (EPSPs) was largely unaffected in old DBA mice. However, spike entrainment during a 100-Hz volley of EPSPs was significantly reduced. This was not a limitation of the ability of bushy cells to fire APs at this stimulus frequency, because entrainment to trains of current pulses was unaffected. Moreover, the decrease in entrainment is not attributable to increased synaptic depression. Surprisingly, the spike latency was 0.46 ms shorter in old DBA mice, and was apparently attributable to a faster conduction velocity, since the evoked excitatory postsynaptic current (EPSC) latency was shorter in old DBA mice as well. We also tested the contribution of the low-voltage-activated K+ conductance (g (KLV)) on the spike latency by using dynamic clamp. Alteration in g (KLV) had little effect on the spike latency. To test whether these changes in DBA mice were simply a result of continued postnatal maturation, we repeated the experiments in CBA mice, a strain that shows normal hearing thresholds through this age range. CBA mice exhibited no reduction in entrainment or increased spike jitter with age. We conclude that the ability of AVCN bushy neurons to reliably follow ANF EPSPs is compromised in a frequency-dependent fashion in hearing-impaired mice. This effect can be best explained by an increase in spike threshold.

Figures

FIG. 1
FIG. 1
Animal age groups and their hearing thresholds. (A) Animals younger than 25 days were considered young, whereas animals older than 40 days were considered old. (B) Thresholds of click evoked auditory brainstem response (ABR) from young and old DBA as well as CBA mice. The click levels were expressed in dB relative to an arbitrary level that was constant across all experiments. Old DBA mice have elevated ABR thresholds.
FIG. 2
FIG. 2
Intrinsic excitability. (A) Type II cell response to a series (150–300 pA) of depolarizing current injection. Bushy neurons typically respond with 1–2 spikes at the onset of current injection. (B) Parameters used to quantify action potential shape. AP height was the difference between resting membrane potential and spike voltage at the peak. AP width was measured at half-height. The maximum rising and falling rates were calculated from the first derivative of the voltage waveform. (C) Type II cell responses to auditory nerve shocks. A train of 20 suprathreshold shocks was delivered to the auditory nerve root at 100, 200, and 300 Hz. Trains were repeated 20 times with intertrial interval of 5 s. Spike latency was measured from the onset of a shock to the peak of the postsynaptic action potential. For each shock in the train, spike temporal jitter was calculated as the standard deviation of the spike latency over 20 trials. Spike entrainment (of a given pulse in the train) was calculated as the fractional number of spike responses over 20 trials. Notice occasional EPSPs that failed to evoke action potentials (arrowhead).
FIG. 3
FIG. 3
Spike latency. (A) Spike latency was plotted for shock trains delivered at 100, 200, and 300 Hz. For clarity, error bars are omitted in the plots for CBA data. The spike latencies from old DBA mice were shorter compared to those from young DBA as well as CBA mice. (B) The action potential latency for the first shock stimulus in the train was different between young and old DBA mice (top panel). In a different set of cells, both AP latency (in current clamp) and evoked EPSC latency (in voltage clamp) were recorded from the same cells. There was a strong correlation between spike latency and EPSC latency (r= 0.72, p< 0.01; middle panel). However, action potential latency was not correlated to the EPSC amplitude (lower panel).
FIG. 4
FIG. 4
Effect of gKLV on spike latency. (A) Total outward K+ currents recorded in the relatively negative voltage range −85 to −30 mV from a bushy cell. Addition of 30 nM α-dendrotoxin reduced the amplitude of the steady-state current (measured at the end of the voltage steps, ▾). (B) Subtracting 20 nS, gKLV converted a bushy cell from single onset spike response to multiple spiking when challenged with large depolarizing currents. Top panels: raster plots of different trials with injected currents ranging from −400 to 600 pA in 50-pA steps. (C) No significant shift in spike latency was observed when altering gKLV between −20 and +20 nS.
FIG. 5
FIG. 5
Spike timing jitter. (A) There was no difference in the first spike jitter between young and old DBA mice. Young CBA mice tended to have smaller first spike jitter, although this was not significant. (B) Normalized spike jitter in DBA mice for shocks delivered at 100 Hz. When spike jitter was normalized to the corresponding spike latency in the train, no difference was observed between young and old DBA mice. (C) Group data of spike jitter at 100, 200, and 300 Hz shock frequencies. Spike jitter was slightly better in old than young DBA mice in all three shock frequencies. The spike jitter became progressively worse and varied more widely within the train for all shock frequencies.
FIG. 6
FIG. 6
Spike entrainment. (A) At 100 Hz, there was a significant difference in entrainment between young and old DBA mice. The mean entrainment for the 11th–20th shocks was significantly lower in old DBA mice than in young DBA mice (inset), but not significantly different between young and old CBA mice. (B) Entrainment at 200 Hz. A larger entrainment decline was seen at 200 Hz shock (notice the different ordinate scale). No difference in entrainment was observed between young and old DBA mice. (C) Entrainment at 300 Hz. Despite an entrainment index below 0.5, cells continue to show reliable firing with current injection (inset). The interaction between synaptic depression and postsynaptic spike refractory produces an alternating pattern of spikes. Inset: responses to current pulses (top) and auditory nerve shocks (bottom) are compared in one cell.
FIG. 7
FIG. 7
Synaptic depression in DBA mice. Synaptic depression was measured by normalizing EPSC amplitudes to the first EPSC in the train. There was no difference between young and old DBA mice. Inset: final depression levels for 200 and 300 Hz shocks.

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