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- Title
Genetic tools for studying cochlear inhibition.
- Authors
Slika, Eleftheria; Fuchs, Paul Albert
- Abstract
Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique a9a10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function a9L9'T nAChR into a9-knockout mice. Continued progress with "efferent gene therapy" will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged a9 or a10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis.
- Subjects
HAIR cells; NICOTINIC acetylcholine receptors; ACOUSTIC trauma; COCHLEA physiology; NICOTINIC receptors; COCHLEAR nucleus; GENETIC models; GENE expression
- Publication
Frontiers in Cellular Neuroscience, 2024, p1
- ISSN
1662-5102
- Publication type
Article
- DOI
10.3389/fncel.2024.1372948