Otoferlin Is Critical for a Highly Sensitive and Linear Calcium-Dependent Exocytosis at Vestibular Hair Cell Ribbon Synapses

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Abstract
Otoferlin, a C2-domain-containing Ca2+binding protein, is required for synaptic exocytosis in auditory hair cells. However, its exact role remains essentially unknown. Intriguingly enough, no balance defect has been observed in otoferlin-deficient (Otof−/−) mice. Here, we show that the vestibular nerve compound action potentials evoked during transient linear acceleration ramps inOtof−/−mice display higher threshold, lower amplitude, and increased latency compared with wild-type mice. Using patch-clamp capacitance measurement in intact utricles, we show that type I and type II hair cells display a remarkable linear transfer function between Ca2+entry, flowing through voltage-activated Ca2+channels, and exocytosis. This linear Ca2+dependence was observed when changing the Ca2+channel open probability or the Ca2+flux per channel during various test potentials. InOtof−/−hair cells, exocytosis displays slower kinetics, reduced Ca2+sensitivity, and nonlinear Ca2+dependence, despite morphologically normal synapses and normal Ca2+currents. We conclude that otoferlin is essential for a high-affinity Ca2+sensor function that allows efficient and linear encoding of low-intensity stimuli at the vestibular hair cell synapse.