Assessment of the expression and role of the {alpha}1 nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea

Hair cell (HC) activity in the mammalian cochlea is modulated by cholinergic efferent inputs from the brainstem. These inhibitory inputs are mediated by calcium-permeable nicotinic acetylcholine receptors (nAChRs) containing α9 and α10 subunits and by subsequent activation of calcium-dependent potassium channels. Intriguingly, mRNAs of α1 and nAChRs, subunits of the 'muscle-type' nAChR have also been found in developing HCs (Cai et al. 2015; Scheffer et al. 2007; Sinkkonen et al. 2011) prompting proposals that another type of nAChR is present and may be critical during early synaptic development. Mouse genetics, histochemistry, pharmacology and whole-cell recording approaches were combined to test the role of α1 nAChR subunit in HC efferent synapse formation and cholinergic function. The onset of α1 mRNA expression in mouse HCs was found to coincide with the onset of the ACh response and efferent synaptic function. However, in mouse inner hair cells (IHCs) no response to the muscle-type nAChR agonists (±)-anatoxin A, (±)-epibatidine, (-)-nicotine or DMPP was detected, arguing against the presence of an independent functional α1-containing muscle-type nAChR in IHCs. In α1 deficient mice, no obvious change of IHC efferent innervation was detected at E18, contrary to the hyperinnervation observed at the neuromuscular junction. Additionally, ACh response and efferent synaptic activity were detectable in α1 deficient IHCs, suggesting that α1 is not necessary for assembly and membrane targeting of nAChRs, or for efferent synapse formation in IHCs.

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