Gating 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 Ca<sup>2+</sup> channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human Ca<sub>V</sub>1.3<sup>A749G</sup> mutation that causes low-voltage Ca<sup>2+</sup> channel activation. We demonstrate activation of Ca<sup>2+</sup> influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of Ca<sub>V</sub>1.3<sup>A749G/A749G</sup> mice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca<sup>2+</sup> channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of Ca<sub>V</sub>1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.
Authors
- Nare Karagulyan
- Nicola Strenzke (ORCID: https://orcid.org/0000-0003-1673-1046)
- Susann Michanski (ORCID: https://orcid.org/0000-0001-5893-1981)
- Nadine J. Ortner (ORCID: https://orcid.org/0000-0003-3882-3283)
- Tobias Moser (ORCID: https://orcid.org/0000-0001-7145-0533)
- Jörg Striessnig (ORCID: https://orcid.org/0000-0002-9406-7120)
- Anupriya Thirumalai (ORCID: https://orcid.org/0000-0002-3624-0343)
- Yunfeng Hua (ORCID: https://orcid.org/0000-0003-0072-7122)
- Yumeng Qi (ORCID: https://orcid.org/0000-0003-0196-6846)
- Carolin Wichmann (ORCID: https://orcid.org/0000-0001-8868-8716)
- Haoyu Wang (ORCID: https://orcid.org/0000-0001-6964-6756)
- Qinghua Fang (ORCID: https://orcid.org/0000-0002-3448-5582)
Institutions
- Innsbruck Medical University (AT)
- Shanghai Jiao Tong University (CN)
- Universität Innsbruck (AT)
- Shanghai Ninth People's Hospital (CN)
- Universitätsmedizin Göttingen (DE)
- European Neuroscience Institute Göttingen (DE)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Max Planck Institute of Experimental Medicine (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1126/sciadv.adu7898
- Citations
- 6
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 8.79