O’Connor, A.P., Amariutei, A.E., Zanella, A. et al. (9 more authors) (2024) In vivo AAV9-Myo7a gene rescue restores hearing and cholinergic efferent innervation in inner hair cells. JCI Insight, 9 (23). e182138. ISSN 2379-3708
Abstract
In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear — but not the medial olivocochlear — efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV-Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024, O’Connor et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | Aging; Gene therapy; Genetic diseases; Mouse models; Neuroscience; Animals; Hair Cells, Auditory, Inner; Dependovirus; Mice; Myosin VIIa; Hearing; Cochlea; Male; Spiral Ganglion; Genetic Therapy; Female; Genetic Vectors; Cholinergic Neurons |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/T004991/1 WELLCOME TRUST (THE) 224326/Z/21/Z BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/X000567/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Jan 2025 10:56 |
Last Modified: | 09 Jan 2025 10:56 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Refereed: | Yes |
Identification Number: | 10.1172/jci.insight.182138 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:221564 |