Gradients and Modulation of K+ Channels Optimize Temporal Accuracy in Networks of Auditory Neurons

Accurate timing of action potentials is required for neurons in auditory brainstem nuclei to encode the frequency and phase of incoming sound stimuli. Many such neurons express “high threshold” Kv3-family channels that are required for firing at high rates (>∼200 Hz). Kv3 channels are expressed in gradients along the medial-lateral tonotopic axis of the nuclei. Numerical simulations of auditory brainstem neurons were used to calculate the input-output relations of ensembles of 1–50 neurons, stimulated at rates between 100–1500 Hz. Individual neurons with different levels of potassium currents differ in their ability to follow specific rates of stimulation but all perform poorly when the stimulus rate is greater than the maximal firing rate of the neurons. The temporal accuracy of the combined synaptic output of an ensemble is, however, enhanced by the presence of gradients in Kv3 channel levels over that measured when neurons express uniform levels of channels. Surprisingly, at high rates of stimulation, temporal accuracy is also enhanced by the occurrence of random spontaneous activity, such as is normally observed in the absence of sound stimulation. For any pattern of stimulation, however, greatest accuracy is observed when, in the presence of spontaneous activity, the levels of potassium conductance in all of the neurons is adjusted to that found in the subset of neurons that respond better than their neighbors. This optimization of response by adjusting the K+ conductance occurs for stimulus patterns containing either single and or multiple frequencies in the phase-locking range. The findings suggest that gradients of channel expression are required for normal auditory processing and that changes in levels of potassium currents across the nuclei, by mechanisms such as protein phosphorylation and rapid changes in channel synthesis, adapt the nuclei to the ongoing auditory environment

Calcium Balance and Mechanotransduction in Rat Cochlear Hair Cells

Auditory transduction occurs by opening of Ca2+-permeable mechanotransducer (MT) channels in hair cell stereociliary bundles. Ca2+ clearance from bundles was followed in rat outer hair cells (OHCs) using fast imaging of fluorescent indicators. Bundle deflection caused a rapid rise in Ca2+ that decayed after the stimulus, with a time constant of about 50 ms. The time constant was increased by blocking Ca2+ uptake into the subcuticular plate mitochondria or by inhibiting the hair bundle plasma membrane Ca2+ ATPase (PMCA) pump. Such manipulations raised intracellular Ca2+ and desensitized the MT channels. Measurement of the electrogenic PMCA pump current, which saturated at 18 pA with increasing Ca2+ loads, indicated a maximum Ca2+ extrusion rate of 3.7 fmol·s−1. The amplitude of the Ca2+ transient decreased in proportion to the Ca2+ concentration bathing the bundle and in artificial endolymph (160 mM K+, 20 μM Ca2+), Ca2+ carried 0.2% of the MT current. Nevertheless, MT currents in endolymph displayed fast adaptation with a submillisecond time constant. In endolymph, roughly 40% of the MT current was activated at rest when using 1 mM intracellular BAPTA compared with 12% with 1 mM EGTA, which enabled estimation of the in vivo Ca2+ load as 3 pA at rest. The results were reproduced by a model of hair bundle Ca2+ diffusion, showing that the measured PMCA pump density could handle Ca2+ loads incurred from resting and maximal MT currents in endolymph. The model also indicated the endogenous mobile buffer was equivalent to 1 mM BAPTA