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

TARANDA J; MAISON, S.F; BALLESTERO J; KATZ E; SAVINO J; VETTER D; BOULTER J; LIBERMAN MC; FUCHS PA; ELGOYHEN AB

PLOS BIOLOGY

PUBLIC LIBRARY SCIENCE

Año: 2009 p. 71 - 83

1544-9173

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 at position 9´ of the second transmembrane domain of the a9 nicotinic cholinergic subunit, rendering a9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9´T allele produced a three-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 a9a10 hair cell nicotinic receptor. Importantly, relative to their wild type littermates, Chrna9L9´T/L9´T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter a9a10 receptor gating has provided an animal model in which efferent inhibition is not only more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.