Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism
Abstract 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 div...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410776 |
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| author | Mathilde Gagliardini Sabrina Mechaussier Carolina Campos Pina Monica Morais Olivier Postal Philippe Jean Typhaine Dupont Amrit Singh‐Estivalet Shéhanie Udugampolage Cyril Scandola Elisabeth Verpy Baptiste Libé‐Philippot Talya C. Inbar Joanna Schwenkgrub Carla Maria Barbosa Spinola Raphaël Etournay Aziz El‐Amraoui Brice Bathellier Adeline Mallet Sedigheh Delmaghani Fabrice Giraudet Christine Petit Boris Gourévitch Paul Avan Nicolas Michalski |
| author_facet | Mathilde Gagliardini Sabrina Mechaussier Carolina Campos Pina Monica Morais Olivier Postal Philippe Jean Typhaine Dupont Amrit Singh‐Estivalet Shéhanie Udugampolage Cyril Scandola Elisabeth Verpy Baptiste Libé‐Philippot Talya C. Inbar Joanna Schwenkgrub Carla Maria Barbosa Spinola Raphaël Etournay Aziz El‐Amraoui Brice Bathellier Adeline Mallet Sedigheh Delmaghani Fabrice Giraudet Christine Petit Boris Gourévitch Paul Avan Nicolas Michalski |
| author_sort | Mathilde Gagliardini |
| collection | DOAJ |
| description | Abstract 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+/− 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+/− 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. |
| format | Article |
| id | doaj-art-8b34654de16f4cbbb72122f6952284d1 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-8b34654de16f4cbbb72122f6952284d12025-08-20T03:13:27ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202410776Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy MechanismMathilde Gagliardini0Sabrina Mechaussier1Carolina Campos Pina2Monica Morais3Olivier Postal4Philippe Jean5Typhaine Dupont6Amrit Singh‐Estivalet7Shéhanie Udugampolage8Cyril Scandola9Elisabeth Verpy10Baptiste Libé‐Philippot11Talya C. Inbar12Joanna Schwenkgrub13Carla Maria Barbosa Spinola14Raphaël Etournay15Aziz El‐Amraoui16Brice Bathellier17Adeline Mallet18Sedigheh Delmaghani19Fabrice Giraudet20Christine Petit21Boris Gourévitch22Paul Avan23Nicolas Michalski24Université Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect, Auditory Therapies Innovation Laboratory Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceInstitut Pasteur Université Paris Cité Ultrastructural Bioimaging Unit Paris F‐75015 FranceInstitut Pasteur IUF, Université Paris Cité, Human Genetics and Cognitive Functions Paris F‐75015 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Auditory System Dynamics and Multisensory Processing Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Cochlear Development and Therapeutic Perspectives Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Cochlear Development and Therapeutic Perspectives Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect, Progressive Sensory Disorders Pathophysiology and Therapy Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Auditory System Dynamics and Multisensory Processing Paris F‐75012 FranceInstitut Pasteur Université Paris Cité Ultrastructural Bioimaging Unit Paris F‐75015 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect, Progressive Sensory Disorders Pathophysiology and Therapy Paris F‐75012 FranceLaboratoire de Biophysique Neurosensorielle, INSERM 1107 Université Clermont Auvergne Clermont‐Ferrand F‐63000 FranceUniversité Paris Cité Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect, Auditory Therapies Innovation Laboratory Paris F‐75012 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceLaboratoire de Biophysique Neurosensorielle, INSERM 1107 Université Clermont Auvergne Clermont‐Ferrand F‐63000 FranceUniversité Paris Cité, Institut Pasteur, AP‐HP, INSERM, CNRS, Fondation Pour l'Audition, Institut de l'Audition, IHU reConnect Plasticity of Central Auditory Circuits Paris F‐75012 FranceAbstract 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+/− 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+/− 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.https://doi.org/10.1002/advs.202410776auditory neuropathylow spontaneous rate spiral ganglion neuronsmiddle ear muscle reflexOtogelin‐likereemerging auditory brainstem responses |
| spellingShingle | Mathilde Gagliardini Sabrina Mechaussier Carolina Campos Pina Monica Morais Olivier Postal Philippe Jean Typhaine Dupont Amrit Singh‐Estivalet Shéhanie Udugampolage Cyril Scandola Elisabeth Verpy Baptiste Libé‐Philippot Talya C. Inbar Joanna Schwenkgrub Carla Maria Barbosa Spinola Raphaël Etournay Aziz El‐Amraoui Brice Bathellier Adeline Mallet Sedigheh Delmaghani Fabrice Giraudet Christine Petit Boris Gourévitch Paul Avan Nicolas Michalski Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism Advanced Science auditory neuropathy low spontaneous rate spiral ganglion neurons middle ear muscle reflex Otogelin‐like reemerging auditory brainstem responses |
| title | Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism |
| title_full | Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism |
| title_fullStr | Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism |
| title_full_unstemmed | Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism |
| title_short | Deciphering Auditory Hyperexcitability in Otogl Mutant Mice Unravels an Auditory Neuropathy Mechanism |
| title_sort | deciphering auditory hyperexcitability in otogl mutant mice unravels an auditory neuropathy mechanism |
| topic | auditory neuropathy low spontaneous rate spiral ganglion neurons middle ear muscle reflex Otogelin‐like reemerging auditory brainstem responses |
| url | https://doi.org/10.1002/advs.202410776 |
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