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bioRxiv · 10.1101/2025.10.15.682551

Persistence of vestibular function in the absence of glutamatergic transmission from hair cells

Mukhopadhyay, M.·Modgekar, R.·Yang-Hood, A.·Ohlemiller, K. K.·Militchin, V.·Xiao, M.·Shen, Z.·Rensing, N.·Wong, M.·Lee, S. J.·Seal, R. P.·Warchol, M. E.·Maloney, S. E.·Yuede, C. M.·Rutherford, M. A.·Pangrsic, T.
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Abstract

Quantal synaptic transmission in vestibular end-organs is glutamatergic. Although genetic deletion of Slc17a8 (termed Vglut3) leads to deafness in mice, the dependence of vestibular function on VGLUT3-mediated quantal transmission is unknown. Here, we investigated the vestibular phenotype of Vglut3-/- mice at the cellular, systems, and behavioral levels. The type-II vestibular hair cells (VHCs) in Vglut3+/+mice were strongly immunoreactive for VGLUT3, while type-I VHCs showed poor immunoreactivity. In Vglut3-/- mice quantal synaptic transmission in utricular calyces was reduced in rate and amplitude by > 95%. In vivo recordings of spontaneous activity in the vestibular nerve revealed similar action potential rates and regularity in Vglut3+/+and Vglut3-/- mice, suggesting a divergent underlying mechanism compared to the silent Vglut3-/- auditory nerve. In behavioral studies, Vglut3-/- mice did not exhibit considerable sensorimotor or balance deficits. Collectively, these data support the view that non-quantal transmission is the predominant mode of neurotransmission between type I VHCs and vestibular calyceal afferent neurons. We propose that non-quantal transmission alone underlies the apparently normal vestibular nerve physiology and behavioral function in Vglut3-/- mice.

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Mukhopadhyay, M., Modgekar, R., Yang-Hood, A., Ohlemiller, K. K., Militchin, V., Xiao, M., Shen, Z., Rensing, N., Wong, M., Lee, S. J., Seal, R. P., Warchol, M. E., Maloney, S. E., Yuede, C. M., Rutherford, M. A., Pangrsic, T.. 2025-10-15. Persistence of vestibular function in the absence of glutamatergic transmission from hair cells. https://doi.org/10.1101/2025.10.15.682551

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