Deciphering Auditory Hyperexcitability in <i>Otogl</i> Mutant Mice Unravels an Auditory Neuropathy Mechanism
Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin-like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl<sup>+/-</sup> mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl<sup>+/-</sup> mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability.
Authors
- Carolina Campos Pina (ORCID: https://orcid.org/0000-0003-0105-2198)
- Raphaël Etournay (ORCID: https://orcid.org/0000-0002-2441-9274)
- Typhaine Dupont (ORCID: https://orcid.org/0000-0001-5497-6568)
- Brice Bathellier (ORCID: https://orcid.org/0000-0001-9211-1960)
- Adeline Mallet (ORCID: https://orcid.org/0000-0003-1604-7308)
- Talya C. Inbar
- Baptiste Libé‐Philippot (ORCID: https://orcid.org/0000-0001-8283-804X)
- A. Amraoui (ORCID: https://orcid.org/0000-0003-2692-4984)
- Mónica Morais (ORCID: https://orcid.org/0000-0003-3226-3828)
- Mathilde Gagliardini
- Joanna Schwenkgrub (ORCID: https://orcid.org/0000-0002-9695-9050)
- Sabrina Méchaussier (ORCID: https://orcid.org/0000-0002-3801-2416)
- Olivier Postal (ORCID: https://orcid.org/0000-0002-6911-7552)
- Sedigheh Delmaghani (ORCID: https://orcid.org/0000-0003-2092-5097)
- Philippe Jean (ORCID: https://orcid.org/0000-0001-5325-1370)
- Nicolas Michalski (ORCID: https://orcid.org/0000-0002-1287-2709)
- Boris Gourévitch (ORCID: https://orcid.org/0000-0001-6742-8739)
- Paul Avan (ORCID: https://orcid.org/0000-0003-1054-1479)
- Christine Petit
- Cyril Scandola (ORCID: https://orcid.org/0000-0002-5305-9095)
- Fabrice Giraudet (ORCID: https://orcid.org/0000-0001-7816-7503)
- Amrit Singh‐Estivalet (ORCID: https://orcid.org/0000-0001-9932-6438)
- Elisabeth Verpy (ORCID: https://orcid.org/0000-0002-5269-0854)
- Carla Maria Barbosa Spinola (ORCID: https://orcid.org/0000-0001-8608-0723)
- Shéhanie Udugampolage
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Sorbonne Nouvelle (FR)
- Collège de France (FR)
- Université Clermont Auvergne (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Cochlear (France) (FR)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1002/advs.202410776
- Citations
- 3
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 4.39
Funders
- European Molecular Biology Organization
- Fondation Pour l'Audition