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

JULIAN TARANDA; STEPHAN MAISON; JIMENA BALLESTERO; ELEONORA KATZ; JESSICA SAVINO; DOUGLAS E. VETTER; JIM BOULTER; M. CHARLES LIBERMAN; PAUL A. FUCHS; ANA BELÉN ELGOYHEN

PLOS BIOLOGY

PUBLIC LIBRARY SCIENCE

Año: 2009 vol. 7 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 effectsare  increased,  and  we  assess  the  consequences  of  this  manipulation  on  cochlear  function.  We  generated  the Chrna9L99T line of knockin mice with a threonine for leucine change (L99T) at position 99 of the second transmembrane domain  of  the  alpha9  nicotinic  cholinergic  subunit,  rendering  alpha9-containing  receptors  that  were  hypersensitive  toacetylcholine and had slower desensitization kinetics. The Chrna9L99T allele produced a 3-fold prolongation of efferent synaptic  currents  in  vitro.  In  vivo,  Chrna9L99T  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, Chrna9L99T/L99T 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.