Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells

Tina Pangšrič, Livia Lasarow, Kirsten Reuter, Hideki Takago, Martin Schwander, Dietmar Riedel, Thomas Frank, Lisa M. Tarantino, Janice S. Bailey, Nicola Strenzke, Nils Brose, Ulrich Müller, Ellen Reisinger, Tobias Moser

Research output: Contribution to journalArticle

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 C2F 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), Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)869-876
Number of pages8
JournalNature neuroscience
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Pangšrič, T., Lasarow, L., Reuter, K., Takago, H., Schwander, M., Riedel, D., Frank, T., Tarantino, L. M., Bailey, J. S., Strenzke, N., Brose, N., Müller, U., Reisinger, E., & Moser, T. (2010). Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells. Nature neuroscience, 13(7), 869-876. https://doi.org/10.1038/nn.2578