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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.12.612688
preprint
1
Article
Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas
Slika Eleftheria http://orcid.org/0000-0001-9128-5125

Fuchs Paul A.
Wood Megan Beers
15 9 2024
2024.09.12.612688https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.09.12.612688
nihpp-2024.09.12.612688.pdf
Abstract

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9) 2 (α10) 3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (α9L9’T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9’T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, α9L9’T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of α9L9’T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed α9L9’T combines effectively with native α9 and α10 subunits to mitigate NIHL in wildtype cochleas.

One Sentence Summary

Viral transduction of a gain-of-function nAChR enhances the native cholinergic inhibition to protect the cochlea from noise-induced hearing loss.
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