Otoferlin is critical for a highly sensitive and linear calcium-dependent exocytosis at vestibular hair cell ribbon synapses

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 in Otof-/- 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-activatedCa2+channels,andexocytosis. This linearCa2+dependencewasobservedwhenchanging theCa 2+channel open probability or the Ca2+flux per channel during various test potentials. In Otof-/-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. Copyright © 2009 Society for Neuroscience.