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bioRxiv · 10.1101/2025.08.06.668943

Functional contributions of quantal and non-quantal hair cell synaptic transmission in the vestibular periphery

Zhou, D.·Yu, Z.·Kodama, T.·Schoo, W.·du Lac, S.·Glowatzki, E.·Sadeghi, S. G.
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Abstract

Information about head motion and gravity is conveyed to the brain by vestibular nerve afferents which are subdivided by their spontaneous firing properties into regular and irregular subtypes thought to be differentially responsible for vestibulo-ocular vs vestibulo-spinal reflexes. In the vestibular periphery, afferents make glutamatergic synapses with type II hair cells (HCs) in all vertebrates. During the evolutionary transition to land, however, amniotes (reptiles, birds, and mammals) additionally developed type I vestibular HCs in which unique calyceal afferent terminals cover the basolateral walls of one or more HCs, enabling a nonquantal (NQ) form of synaptic transmission. Most afferents receive inputs from both types of HCs, but the roles of type I vs type II HCs in generating vestibular afferent firing patterns and behaviors remains unclear. Using optogenetics in mice (both sexes), we confirm that stimulation of type II HCs drives conventional quantal glutamatergic transmission, whereas type I HC stimulation evokes nonquantal responses. In mice with disrupted glutamatergic quantal transmission, NQ transmission effectively drove afferent responses to a wide range of head movement frequencies, as assessed by both vestibular sensory evoked potentials and the vestibulo-ocular reflex. Although the distribution of afferent discharge regularity was unaffected, loss of glutamatergic transmission impaired detection of gravity as evidenced by abnormal contact righting reflex behavior. These results indicate that nonquantal glutamatergic transmission from type I HCs is sufficient to generate normal afferent firing patterns and dynamic vestibular behaviors and that glutamatergic release from type II HCs is required for the detection of gravity. Significance StatementThe vestibular system enables balance and spatial orientation by detecting head movements and gravity. During vertebrate evolution, amniotes developed a unique form of synaptic communication--non-quantal (NQ) transmission--between type I hair cells and calyceal afferent nerve fibers in vestibular sensors. This study reveals that NQ transmission can robustly drive vestibular responses across a wide stimulus range, even in the absence of conventional glutamate-based (quantal) signaling. Using electrophysiology, optogenetics and behavioral assays, we show that NQ and quantal transmission serve distinct but complementary roles: NQ supports rapid, broad-range signaling, while quantal transmission is critical for precise gravity detection. These findings highlight how evolutionary innovations in synaptic transmission enhance vestibular function, contributing to our understanding of balance disorders and sensory processing.

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Zhou, D., Yu, Z., Kodama, T., Schoo, W., du Lac, S., Glowatzki, E., Sadeghi, S. G.. 2025-08-09. Functional contributions of quantal and non-quantal hair cell synaptic transmission in the vestibular periphery. https://doi.org/10.1101/2025.08.06.668943

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