A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.

TitleA point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.
Publication TypeJournal Article
Year of Publication2009
AuthorsTaranda, J, Maison SF, Ballestero JA, Katz E, Savino J, Vetter DE, Boulter J, Liberman CM, Fuchs PA, Elgoyhen BA
JournalPLoS biology
Volume7
Issue1
Paginatione18
Date Published2009 Jan 20
ISSN1545-7885
Keywordsacetylcholine, Animals, Auditory Pathways, Auditory Threshold, Cholinergic Agents, Cochlea, Disease Models, Animal, Feedback, Physiological, Hair Cells, Auditory, Hearing Loss, Sensorineural, Mice, Mice, Mutant Strains, Neurons, Efferent, Point Mutation, Potassium Channels, Receptors, Nicotinic, Signal Transduction, Synapses
Abstract

The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T) at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T) mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

Alternate JournalPLoS Biol.