Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse

Summary The auditory inner hair cell (IHC) ribbon synapse operates with an exceptional temporal precision and maintains a high level of neurotransmitter release. However, the molecular mechanisms underlying IHC synaptic exocytosis are largely unknown. We studied otoferlin, a predicted C2-domain transmembrane protein, which is defective in a recessive form of human deafness. We show that otoferlin expression in the hair cells correlates with afferent synaptogenesis and find that otoferlin localizes to ribbon-associated synaptic vesicles. Otoferlin binds Ca 2+ and displays Ca 2+ -dependent interactions with the SNARE proteins syntaxin1 and SNAP25. Otoferlin deficient mice ( Otof −/− ) are profoundly deaf. Exocytosis in Otof −/− IHCs is almost completely abolished, despite normal ribbon synapse morphogenesis and Ca 2+ current. Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca 2+ sensor triggering membrane fusion at the IHC ribbon synapse.