Abstract
Cholinergic efferent neurons modulate sensory signaling in the peripheral vestibular system, but the cellular mechanisms underlying this modulation remain incompletely understood. In mammalian vestibular organs, type II hair cells (HC-II) receive efferent input and express α9α10-containing nicotinic acetylcholine receptors (nAChRs) that activate SK potassium channels and produce rapid hyperpolarization. Here, we examined the functional role of mAChRs in mouse vestibular HC-II using whole cell patch clamp recordings in whole tissue preparations of crista ampularis (P13-P17, male and female mice). Activation of mAChRs with oxotremorine-M inhibited voltage dependent outward currents, with the largest effects at depolarized membrane potentials. Further experiments revealed that this effect was mediated by inhibition of large conductance potassium (BK) channels: the BK antagonist iberiotoxin mimicked and occluded the muscarinic effect and muscarinic suppression was absent in mice with BK channel mutations. In contrast, blockade of SK channels with apamin did not prevent the muscarinic effect, indicating that mAChR signaling specifically targets BK mediated currents. In current clamp recordings, mAChR activation enhanced depolarization during strong current injections, consistent with increased hair cell excitability when BK channels were suppressed. These findings identify a previously unrecognized muscarinic efferent pathway in vestibular hair cells and reveal complementary cholinergic mechanisms that suppress responses to weak stimuli while enhancing responses to strong stimulation, providing a cellular basis for dynamic gain control in the vestibular periphery. SIGNIFICANCE STATEMENT: Vestibular efferent signaling shapes how head movements are encoded, but its cellular mechanisms are incompletely understood. While nicotinic acetylcholine receptors are known to reduce excitability of type II vestibular hair cells (HC-II) via small conductance (SK) channels, the role of muscarinic receptors has remained unclear. Here we show that muscarinic receptor activation selectively inhibits large conductance (BK) potassium channels in HC-II, enhancing excitability during strong depolarization. This muscarinic pathway is mechanistically distinct from nicotinic signaling and operates at a different voltage range. Together, these findings reveal a dual efferent control strategy that differentially regulates hair cell responses to slow versus fast head movements, providing new insight into how the vestibular system filters sensory input across dynamic ranges.