Role of α9 Nicotinic ACh Receptor Subunits in the Development and Function of Cochlear Efferent Innervation

Abstract

Cochlear outer hair cells (OHCs) express alpha9 nACh receptors and are contacted by descending, predominately cholinergic, efferent fibers originating in the CNS. Mice carrying a null mutation for the nACh alpha9 gene were produced to investigate its role(s) in auditory processing and development of hair cell innervation. In alpha9 knockout mice, most OHCs were innervated by one large terminal instead of multiple smaller terminals as in wild types, suggesting a role for the nACh alpha9 subunit in development of mature synaptic connections. Alpha9 knockout mice also failed to show suppression of cochlear responses (compound action potentials, distortion product otoacoustic emissions) during efferent fiber activation, demonstrating the key role alpha9 receptors play in mediating the only known effects of the olivocochlear system.

α10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells

“…The signature pharmacology of the nAChR at the efferent olivocochlear hair cell synapse (7,21,22) was sufficiently distinct that before the cloning and characterization of the ␣9 nAChR subunit, none of the extant recombinant nAChRs were likely candidates to fill the role. Since then, however, characterization of recombinant ␣9 nAChRs (14-16) and generation of a transgenic ␣9 Ϫ/Ϫ null mutant mouse (23) has provided a combination of data compelling enough to propose a central role for ␣9-containing nAChRs in the cholinergic biology of mechanosensory hair cells.…”

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…To date, knockout mice have been generated that lack the α3 [191], α4 [108], α5 [183], α6 [19], α7 [123], α9 [177], β2 [129,190], β3 [27], and β4 [190] nAChR subunits, and subsequent research has demonstrated that the deletion of these genes will alter many of the effects of nicotine in mice. Additionally, KI mice with point mutations that produce hypersensitive nAChRs have been generated for the α4 [86,167] and α7 subunits [124].…”

Medial olivocochlear reflex interneurons are located in the posteroventral cochlear nucleus: A kainic acid lesion study in guinea pigs

“…Lateral olivocochlear (LOC) neurons have cell bodies in or around the lateral superior olive and project to afferent fibers near inner hair cells (Warr and Guinan, 1979;Liberman, 1980;Liberman and Brown, 1986;Brown, 1987;Vetter and Mugnaini, 1992;Maison et al, 2003). Cholinergic MOC endings in the cochlea exert their effects by means of a nicotinic receptor (Vetter et al, 1999;Elgoyhen et al, 2001Elgoyhen et al, , 2003 that influences outer hair cell function and alters cochlear responses (Wiederhold and Kiang, 1970;Mountain, 1980;Siegel and Kim, 1982;Brown and Nuttall, 1984). For instance, activation of MOC neurons alters distortion product otoacoustic emissions (DPOAEs), causing rapid amplitude changes in the first several hundred milliseconds after primary-tone onset (Liberman et al, 1996;Kujawa and Liberman, 2001).…”