Hair cells use active zones with different voltage dependence of Ca ²⁺ influx to decompose sounds into complementary neural codes

Abstract

For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca 2+ influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca 2+ influx ranged over ∼20 mV. Ca 2+ influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca 2+ channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca 2+ influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca 2+ influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca 2+ influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca 2+ channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs.auditory system | spiral ganglion neuron | dynamic range | synaptic strength | presynaptic heterogeneity T he auditory system enables us to perceive sound pressures that vary over six orders of magnitude. This is achieved by active amplification of cochlear vibrations at low sound pressures and compression at high sound pressures. The receptor potential of inner hair cells (IHCs) represents the full range (1), whereas each postsynaptic type I spiral ganglion neuron (hereafter termed SGN) encodes only a fraction (2-6). SGNs with comparable frequency tuning but different spontaneous spike rates and sound responses are thought to emanate from neighboring, if not the same, IHC at a given tonotopic position of the organ of Corti (2,5,7,8). Even in silence, IHC active zones (AZs) release glutamate at varying rates, evoking "spontaneous" spiking in SGNs. SGNs with greater spontaneous spike rates respond to softer sounds (highspontaneous rate, low-threshold SGNs), than those with lower spontaneous spike rates (low-spontaneous rate, high-threshold SGNs) (2, 9). This diversity likely underlies the representation of sounds across all audible sound pressure levels in the auditory nerve, to which neural adaptation also contributes (10).How SGN diversity arises is poorly understood. Candidate mechanisms include the heterogeneity of ribbon synapses that differ in pre-and/or postsynaptic properties even within individual IHCs (7,(11)(12)(13)(14). IHC AZs vary in the number (11, 15) and voltage dependence of gating (11) of their Ca 2+ channels regardless of tonotopic position (16). Lateral olivocochlear efferent projections to the SGNs regulate postsynaptic exc...

Enlargement of Ribbons in Zebrafish Hair Cells Increases Calcium Currents But Disrupts Afferent Spontaneous Activity and Timing of Stimulus Onset

“…Recent work in mouse IHCs found that, compared with smaller ribbons, Ca V 1.3 channels at larger ribbons within the same hair cell were activated at more depolarized membrane potentials creating a higher threshold for activation (Ohn et al, 2016). By contrast, we saw a similar activation of the calcium current in transgenic hair cells compared with WT hair cells (Fig.…”

Ca 2+ -binding protein 2 inhibits Ca 2+ -channel inactivation in mouse inner hair cells

“…IHC Ca V 1.3 Ca 2+ channels stand out by reason of their hyperpolarized activation range and modest inactivation (10,18,19,22,45). These properties have been attributed to the molecular composition of the native Ca 2+ -channel complexes that, in addition to the specific pore-forming Ca V 1.3α1 splice variant (46), auxiliary Ca V β2 (6,47), and Ca V α 2 δ2 (7) subunit, also contain interactions partners, such as Rab3-interacting molecule (RIM) (48,49); harmonin (50, 51); calmodulin; and, notably, CaBPs (this study and refs.…”

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

“…In addition, there were differences in the size of the synaptic ribbon, with the ribbons on modiolar side being larger and more elongated; however, the significance of this observation is obscure. Other work has suggested a presynaptic variation such that Cav1.3 Ca 2+ channels on the pillar side may activate at more hyperpolarized potentials than those on the modiolar side, thereby allowing Ca 2+ entry for weaker depolarization (217). At this stage, the origin of the heterogeneity in synaptic sensitivities and related spontaneous activities is not fully understood.…”