Mice Lacking the Alpha9 Subunit of the Nicotinic Acetylcholine Receptor Exhibit Deficits in Frequency Difference Limens and Sound Localization.

Amanda M. Lauer,Karl Kandler,Amanda Clause

doi:10.3389/fncel.2017.00167

Abstract

Sound processing in the cochlea is modulated by cholinergic efferent axons arising from medial olivocochlear neurons in the brainstem. These axons contact outer hair cells in the mature cochlea and inner hair cells during development and activate nicotinic acetylcholine receptors composed of α9 and α10 subunits. The α9 subunit is necessary for mediating the effects of acetylcholine on hair cells as genetic deletion of the α9 subunit results in functional cholinergic de-efferentation of the cochlea. Cholinergic modulation of spontaneous cochlear activity before hearing onset is important for the maturation of central auditory circuits. In α9KO mice, the developmental refinement of inhibitory afferents to the lateral superior olive is disturbed, resulting in decreased tonotopic organization of this sound localization nucleus. In this study, we used behavioral tests to investigate whether the circuit anomalies in α9KO mice correlate with sound localization or sound frequency processing. Using a conditioned lick suppression task to measure sound localization, we found that three out of four α9KO mice showed impaired minimum audible angles. Using a prepulse inhibition of the acoustic startle response paradigm, we found that the ability of α9KO mice to detect sound frequency changes was impaired, whereas their ability to detect sound intensity changes was not. These results demonstrate that cholinergic, nicotinic α9 subunit mediated transmission in the developing cochlear plays an important role in the maturation of hearing.

Highlights

The cochlea encodes sound and transmits auditory information to the brain and receives abundant efferent innervation from the brain
We investigated whether mice lacking the α9 acetylcholine receptor subunit and functional medial olivocochlear (MOC) efferent feedback show impairments in sound localization and sound frequency difference limens
When α9KO mice were tested for frequency difference limens using prepulse inhibition (PPI) of the acoustic startle response (ASR), we observed poorer frequency difference limens but not intensity difference limens in mature mice as well as in mice around hearing onset

Summary

Introduction

The cochlea encodes sound and transmits auditory information to the brain and receives abundant efferent innervation from the brain. The primary function of this cholinergic innervation is to adjust the gain of the cochlear amplifier (Guinan, 1986; Kim, 1986; Housley and Ashmore, 1991; Dallos et al, 1997), as it Hearing Impairments in α9KO Mice acts as an innate efferent feedback system that reduces auditory nerve activity, in noisy environments (Winslow and Sachs, 1987; Guinan, 1996) These MOC system-mediated effects are produced via suppression of cochlear responses to sound, which occurs through hyperpolarization of OHCs. Cholinergic hyperpolarization is accomplished by the activation of nicotinic acetylcholine receptors that consist of α9 and α10 subunits (Elgoyhen et al, 1994, 2001; Blanchet et al, 1996; Dulon and Lenoir, 1996; Evans, 1996; Fuchs, 1996; Lustig, 2006; Ballestero et al, 2011). OHC hyperpolarization induces an electromotile response in these cells that decreases cochlear sensitivity to sound (Fuchs, 1996; Oliver et al, 2000; Goutman et al, 2005). α9 receptor subunits are crucial for functional acetylcholine receptors in hair cells because their genetic deletion eliminates cholinergic OHC hyperpolarization and MOC system-mediated suppression of cochlear activity (Vetter et al, 1999)

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