A sensory cell diversifies its output by varying Ca²⁺influx-release coupling among presynaptic active zones for wide range intensity coding

Abstract

The cochlea encodes sound intensities ranging over six orders of magnitude which is collectively achieved by functionally diverse spiral ganglion neurons (SGNs). However, the mechanisms enabling the SGNs to cover specific fractions of the audible intensity range remain elusive. Here we tested the hypothesis that intensity information, fully contained in the receptor potential of the presynaptic inner hair cell (IHC), is fractionated via heterogeneous synapses. We studied the transfer function of individual active zones (AZs) using dual-color Rhod-FF and iGluSnFR imaging of Ca 2+ and glutamate release. AZs differed in the voltage dependence of release: AZs residing at the IHCs' pillar (abneural) side activate at more hyperpolarized potentials and typically showed tight control of release by few Ca 2+ -channels. We conclude that heterogeneity of voltage dependence and release-site coupling of Ca 2+ -channels among the AZs varies synaptic transfer within individual IHCs and, thereby, likely contributes to the functional diversity of SGNs.

Recent advances in cochlear hair cell nanophysiology: subcellular compartmentalization of electrical signaling in compact sensory cells

“…A negative feedback to presynaptic Ca 2+ influx is mediated by the release of protons during SV exocytosis that partially inhibit the Ca 2+ channels under physiological pH buffering 156 , and a potential modulation of the IHC Ca 2+ channel by lipids 157 , 158 remains to be elucidated. Despite the heterogeneity of the control of exocytosis by Ca 2+ influx among hair cell AZs, the voltage dependence of Ca 2+ influx generally predicts that of SV release 155 . Site-specific trafficking of components of the Ca 2+ channel complex might involve adapter proteins such as Gipc3 126 , and differences in the capacity of tethering multidomain proteins available at the AZ 114 , 120 , 121 likely contribute to the heterogeneous Ca 2+ channel complement.…”

“…Such massive differences in Ca 2+ channel clustering are likely to impact their biophysical properties and the coupling of Ca 2+ influx to SV release. Indeed, recently, it was shown that AZs vary in the control of exocytosis by Ca 2+ influx 155 . However, the expectation that membrane nanodomains with a high density of Ca 2+ channels might present an active local depolarization exceeding the overall hair cell potential seems not to be supported: the voltage dependence of activation does not correlate positively with the maximal Ca 2+ influx 126 .…”

Otoferlin as a multirole Ca2+ signaling protein: from inner ear synapses to cancer pathways

“…organization of Ca V 1.3 calcium channels at each presynaptic active zone has been proposed to determine the firing specificity of the auditory nerve fibers (Özçete and Moser, 2021). Other factors, such as a mechanical tuning of each ribbon, could also participate in the firing frequency characteristic of each auditory fiber (Figures 7-9).…”

Divide and conquer acoustic diversity

“…In a previous paper, it was shown that larger active zones with stronger Ca 2+ influx tend to reside on the modiolar side of IHCs, whereas pillar side synapses presented more hyperpolarized activation ranges for Ca 2+ influx (Ohn et al , 2016). But some aspects of this problem remained an enigma to the field that has now been addressed by Özçete & Moser (2021). In the current study, the authors went one step further by simultaneously imaging, with a dual color approach, a specific Ca 2+ indicator (Rhod‐FF) and a fluorescent “glutamate sniffer”, iGluSnFR, expressed in SGNs.…”

“…Özçete & Moser (2021) provide high‐quality information on Ca 2+ and glutamate signals from single synaptic sites as a function of IHC membrane potential, a way to mimic varying sound intensity stimuli. The authors found heterogeneity in the membrane potential at which Ca 2+ and glutamate signals showed its half maximum activation (V 1/2 ).…”