Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing

Abstract

Little is known about the function of the cholinergic efferents innervating peripheral vestibular hair cells. We measured vestibular sensory evoked potentials (VsEPs) in α9 knockout (KO) mice, α10 KO mice, α7 KO mice, α9/10 and α7/9 double KO mice, and wild-type (WT) controls. We also studied the morphology and ultrastructure of efferent terminals on vestibular hair cells in α9, α10, and α9/10 KOs. Both type I and type ll vestibular hair cells express the α9 and α10 subunits. The efferent boutons on vestibular cells in α9, α10, and α9/10 KOs appeared normal, but a quantitative analysis was not performed. Mean VsEP thresholds were significantly elevated in α9 and α9/10 KO animals. Some α9 and α9/10 KO animals, however, had normal or near-normal thresholds, whereas others were greatly affected. Despite individual variability in threshold responses, latencies were consistently shortened. The double α7/9 KO resulted in decreased variance by normalizing waveforms and latencies. The phenotypes of the α7 and α10 single KOs were identical. Both α7 and α10 KO mice evidenced normal thresholds, decreased activation latencies, and larger amplitudes compared with WT mice. The data suggest a complex interaction of nicotinic acetylcholine receptors (nAChRs) in regulating vestibular afferent gain and activation timing. Although the α9/10 heteromeric nAChR is an important component of vestibular efferent activity, other peripheral or central nAChRs involving the α7 subunit or α10 subunit and α9 homomeric receptors are also important. J. Comp. Neurol. 525:1216-1233, 2017. © 2016 Wiley Periodicals, Inc.

Generation and Characterization of α9 and α10 Nicotinic Acetylcholine Receptor Subunit Knockout Mice on a C57BL/6J Background

“…The results of custom PCR arrays showed that the α9 and α10 transcription in cochlea of the constitutive α9 and α10 KOs, respectively, was eliminated and there was no apparent up-regulation by other nAChR subunits (Figure 9 ). In other publications, we reported that α9 transcript was absent in the retina of our α9 knockout (Smith et al, 2014 ), and that α9 and α10 transcription was absent in vestibular tissue of the respective constitutive KOs (Morley et al, 2017 ).…”

“…Differences in the physiology (this report; Morley et al, 2017 ) between our α9 and α10 constitutive KO mice and the models first described by Elgoyhen et al ( 1994 , 2001 ) may be attributable to genes in the background strains that could modify the phenotypes. Unlike earlier lesioning experiments, behavioral thresholds of the previous α9 KO model did not show any performance deficits in the presence of background noise (May et al, 2002 ).…”

“…The results reported here, however, are consistent with our studies of the vestibular system in our mouse models. We recently reported the analysis of vestibular sensory evoked potentials (VsEPs) in α9, α10, α9α10, α7, and α7α9 knockouts (Morley et al, 2017 ). The results were complex.…”

“…It is typically inferred that α10 is present whenever α9 is detected and that they always assemble, but there are data that suggest that α7 and α10 could form a receptor (Lips et al, 2006 ; Morley et al, 2017 ). Although α9-containing nAChRs are ionotropic, they may also mediate metabolic signaling (Richter et al, 2016 ; Backhaus et al, 2017 ; Zakrzewicz et al, 2017 ).…”

Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype

“…Heteromeric α9α10 nAChRs play an important physiological role in mediating olivocochlear and vestibular neurotransmission. 4,5 Transcripts/protein expression of α9 and/or α10 subunits have been reported in dorsal root ganglion neurons, 6,7 adrenal medulla, 8 and in other non-neuronal cells, such as skin keratinocytes, pituitary pars tuberalis, lymphocytes, macrophages and bladder urothelium. [9][10][11][12][13][14][15] α9-Containing nAChRs are potential targets for the therapy of several disorders or diseases such as ear disorders, chronic pain and pemphigus vulgaris.…”