Olivocochlear Function is Dramatically Increased in Mice with a Point Mutation (L9’T) of the alpha9 Nicotinic Ach Receptor

STÉPHANE F. MAISON; JULIÁN TARANDA; JIMENA A. BALLESTERO; ELEONORA KATZ; JIM BOULTER; PAUL A. FUCHS; DOUGLAS E. VETTER; A. BELÉN ELGOYHEN; CHARLES LIBERMAN

Phoenix, Arizona, USA.

Congreso; Thirty-first annual midwinter research meeting of the Association for research in otolaryngology; 2008

Association for research in otolaryngology (ARO)

Acetylcholine (ACh) is the major neurotransmitter of olivocochlear (OC) efferents. the OC-mediated suppression of outer hair cell (OHC) function and associated cochlear threshold elevation are mediated by alpha9/alpha10 nicotinic ACh receptors (nAChRs). This study investigates the In Vivo effects of a point mutation (L9´T) in the pore region of the alpha9 subunit designed to increase the strength of OC effects by decreasing the desensitization of the channel in the presence of ACh [Plazas et al., British J Pharmacol, 2005]. Cochlear sensitivity in mutants was characterized by measuring 1) ABRs at 7 log-spaced frequencies from 5.6 to 45.2 kHz, 2) DPOAEs evoked by primaries with f2 at the same 7 frequencies, and 3) the magnitude of DPOAE suppression evoked by electric stimulation of the OC bundle. Groups of mice homozygous and heterozygous for the mutation were compared with wildtype littermates.Both ABR and DPOAE thresholds in homozygous knockins were elevated by 5-15 dB across all test frequencies re wildtype suggesting OHC dysfunction. Systemic injectionof strychnine [30 mg/kg], a potent blocker of the alpha9 nAChR, produced a partial rescue of the threshold-shift phenotype, suggesting that baseline OC-mediated suppression was at least partially responsible for the baseline threshold elevation. Correspondingly, the magnitude and time course of OC suppressive effects induced by electric stimulation of the OC bundle weredramatically affected with slower and larger suppression observed in mutants.Given that OC effects are dramatically larger in mutants and OC efferents protect the ear from acoustic injury, this mutation could prove useful in enhancing resistance to acoustic injury.