Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing

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The α9 and α10 nicotinic acetylcholine receptor (nAChR) subunits are members of the subfamily I, epithelial α9 and α10 ion‐gated nicotinic receptor gene family. The α9 and α10 subunits are expressed in the epithelial cells of the vertebrate inner ear, including cochlear outer hair cells (OHCs) in the mature inner ear, cochlear inner hair cells (IHCs) in postnatal animals before the onset of hearing, and vestibular hair cells (Elgoyhen et al., 1994; Hiel et al., 1996; Vetter et al., 1999; Simmons and Morley, 2011). Alpha9 subunit expression has been reported in the lateral line of the trout (Drescher et al., 2004) as well as hair cells in the frog, fish, and turtle (Holt et al., 2006; Jordan et al., 2013); bird (Lustig et al., 1999); rodent (Elgoyhen et al., 1994; Luebke et al., 2005; Simmons and Morley, 2011); and human (Lustig and Peng, 2002).
The α9 and α10 subunits, in at least some species, can form homomeric receptors (Elgoyhen and Franchini, 2011). Functional mammalian α9 homomers have been demonstrated in Xenopus oocytes (Elgoyhen et al., 1994) and in the mouse cochlea (Vetter et al., 2007), but only the α9/10 heteromer is believed to transduce efferent signals in vivo in the cochlea (Elgoyhen et al., 2001; Vetter et al., 2007). The auditory and vestibular efferent neurons and boutons express presynaptic and postsynaptic cholinergic markers (Kong et al., 1994; Holt et al., 2011; Simmons and Morley, 2011), and the endogenous cholinergic receptor in the cochlea has a unique nicotinic pharmacology and physiology identical to that of the α9/10 receptor expressed in Xenopus oocytes (Elgoyhen et al., 1994; Holt et al., 2003).
Alpha9 and α10 nAChR subunit mRNA expression has been reported for both type I and type II vestibular hair cells (Hiel et al., 1996; Simmons and Morley, 2011). Cholinergic efferent axons terminate on type II hair cells as well as the innervating afferent boutons (Holt et al., 2011). Vestibular type I hair cells in the mature mammal, however, are innervated exclusively by a large afferent calyx (Wersäll, 1956; Lysakowski and Goldberg, 2004). These calyces are terminal endings on either calyx‐only or dimorphic afferents. Calyx‐only afferents are found in the central or striolar zone of vestibular sensory epithelia, whereas dimorphic afferents are found throughout the sensory epithelium where they contact both type I and type II hair cells. Finally, bouton‐only afferents contact type II hair cells in the peripheral or extrastriolar zones (Fernandez et al., 1988, 1990). Cholinergic efferent axons terminate on the outer faces of the calyx, but not the type I hair cells directly (Holt et al., 2011). The expression of α9 and α10 in type I hair cells may be attributable to their early innervation by cholinergic efferent axons (Favre and Sans, 1979; Dechesne, 1992). It is not known whether the deletion of the α9 and/or α10 nAChR subunits affects the morphology or innervation pattern of vestibular boutons terminating on vestibular hair cells. It is also not known whether deletion of one or both subunits has a functional consequence. This study investigates the structure and ultrastructure of vestibular efferent boutons and the function of the vestibular afferents in mature wild‐type (WT) C57Bl/6J and in mice with the deletion (knockout; KO) of the α9 nAChR subunit, the α10, or both the α9 and the α10 subunits (double KO). We investigated the possibility that residual 129/sv background genes might modify vestibular physiology in the knockouts. Finally, we investigated whether the deletion of the α7 nAChR subunit, which is heavily expressed in the vestibular brainstem (Happe and Morley, 1998), would modify vestibular physiology in the α9 KO.
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