PMID:20562868

Citation	Pangrsic, T, Lasarow, L, Reuter, K, Takago, H, Schwander, M, Riedel, D, Frank, T, Tarantino, LM, Bailey, JS, Strenzke, N, Brose, N, Müller, U, Reisinger, E and Moser, T (2010) Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells. Nat. Neurosci. 13:869-76
Abstract	Inner hair cell ribbon synapses indefatigably transmit acoustic information. The proteins mediating their fast vesicle replenishment (hundreds of vesicles per s) are unknown. We found that an aspartate to glycine substitution in the C(2)F domain of the synaptic vesicle protein otoferlin impaired hearing by reducing vesicle replenishment in the pachanga mouse model of human deafness DFNB9. In vitro estimates of vesicle docking, the readily releasable vesicle pool (RRP), Ca(2+) signaling and vesicle fusion were normal. Moreover, we observed postsynaptic excitatory currents of variable size and spike generation. However, mutant active zones replenished vesicles at lower rates than wild-type ones and sound-evoked spiking in auditory neurons was sparse and only partially improved during longer interstimulus intervals. We conclude that replenishment does not match the release of vesicles at mutant active zones in vivo and a sufficient standing RRP therefore cannot be maintained. We propose that otoferlin is involved in replenishing synaptic vesicles.
Links	PubMed Online version:10.1038/nn.2578
Keywords	Animals; Calcium Signaling/physiology; Deafness/metabolism; Disease Models, Animal; Excitatory Postsynaptic Potentials/physiology; Hair Cells, Auditory, Inner/metabolism; Hair Cells, Auditory, Inner/ultrastructure; Hearing/physiology; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mice, Neurologic Mutants; Mutation, Missense; Synapses/metabolism; Synapses/ultrastructure; Synaptic Vesicles/genetics; Synaptic Vesicles/metabolism; Synaptic Vesicles/ultrastructure
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:OTOF		GO:0016082: synaptic vesicle priming	ECO:0000315:		P		Figs 4&5.	complete CACAO 5596
MOUSE:OTOF	involved_in	GO:0016082: synaptic vesicle priming	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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