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The Journal of Neuroscience, August 26, 2009, 29(34):10474-10487; doi:10.1523/JNEUROSCI.1009-09.2009

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

Didier Dulon,^1 * Saaid Safieddine,^2 * Sherri M. Jones,³ and Christine Petit^2,4

¹Université Victor Segalen Bordeaux 2, Institut des Neurosciences de Bordeaux, Equipe Neurophysiologie de la Synapse Auditive, Inserm, Unité Mixte de Recherche en Santé 587, Centre Hospitalier Universitaire Hôpital Pellegrin, 33076 Bordeaux, France, ²Institut Pasteur et Université Pierre et Marie Curie, Unité de Génétique et Physiologie de l'Audition, Inserm Unité Mixte de Recherche en Santé 587, 75015 Paris, France, ³Department of Communication Sciences and Disorders, East Carolina University, Greenville, North Carolina 27858, and ⁴Collège de France, 75005 Paris, France

Correspondence should be addressed to Didier Dulon, Université Victor Segalen Bordeaux 2, Institut des Neurosciences de Bordeaux, Equipe Neurophysiologie de la Synapse Auditive, Inserm, Unité Mixte de Recherche en Santé 587, Centre Hospitalier Universitaire Hôpital Pellegrin, 33076 Bordeaux, France. Email: didier.dulon{at}inserm.fr

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-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. 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.

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Received March 1, 2009; revised July 7, 2009; accepted July 8, 2009.

Correspondence should be addressed to Didier Dulon, Université Victor Segalen Bordeaux 2, Institut des Neurosciences de Bordeaux, Equipe Neurophysiologie de la Synapse Auditive, Inserm, Unité Mixte de Recherche en Santé 587, Centre Hospitalier Universitaire Hôpital Pellegrin, 33076 Bordeaux, France. Email: didier.dulon{at}inserm.fr

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