biostudies-literatureKaragulyan NEuropean Research Councileadu7898https://www.ebi.ac.uk/biostudies/studies/S-EPMC12225641biostudies-literatureUnknown11(25)Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca²⁺ channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human Ca_V1.3^A749G mutation that causes low-voltage Ca²⁺ channel activation. We demonstrate activation of Ca²⁺ influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of Ca_V1.3^A749G/A749G mice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca²⁺ channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of Ca_V1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.Science advancesGating of hair cell Ca<sup>2+</sup> channels governs the activity of cochlear neurons.PMC12225641101054467Wichmann CHua YKaragulyan NStrenzke NMichanski SStriessnig JQi YFang QThirumalai AWang HOrtner NJMoser TfalseGating of hair cell Ca<sup>2+</sup> channels governs the activity of cochlear neurons.Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca²⁺ channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human Ca_V1.3^A749G mutation that causes low-voltage Ca²⁺ channel activation. We demonstrate activation of Ca²⁺ influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of Ca_V1.3^A749G/A749G mice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca²⁺ channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of Ca_V1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.2025-01-01T00:00:00Z2025 Jun2026-06-30T03:25:29.801Z2026-06-30T03:20:50.224ZS-EPMC122256414053201010.1126/sciadv.adu7898