Mammalian cochlear inner hair cells (IHCs) are specialized for the dynamic coding of continuous and finely graded sound signals. This ability is largely conferred by the linear Ca2+ dependence of neurotransmitter release at their synapses, which is also a feature of visual and olfactory systems. The prevailing hypothesis is that linearity in IHCs occurs through a developmental change in the Ca2+ sensitivity of synaptic vesicle fusion from the nonlinear (high order) Ca2+ dependence of immature spiking cells. However, the nature of the Ca2+ sensor(s) of vesicle fusion at hair cell synapses is unknown. We found that synaptotagmin IV was essential for establishing the linear exocytotic Ca2+ dependence in adult rodent IHCs and immature outer hair cells. Moreover, the expression of the hitherto undetected synaptotagmins I and II correlated with a high-order Ca2+ dependence in IHCs. We propose that the differential expression of synaptotagmins determines the characteristic Ca2+ sensitivity of vesicle fusion at hair cell synapses.
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We would like to thank M.C. Holley and E. Smythe for their critical feedback on an earlier version of the manuscript. We would also like to thank A. Catapang for help with genotyping, M. Cardwell and A. Davids for their assistance with the breeding of Syt IV animals, and K. Rohbock and S. Kasperek for their technical assistance with the immunolabeling experiments. The rSytIV pIE construct was obtained from Addgene. This work was supported by grants from the Wellcome Trust, Deafness Research UK, University of Sheffield Devolved Funds and The Royal Society to W.M., Deutsche Forschungsgameinschft 316-4-1 to M.K., and the Baden-Württemberg Graduate Programme of the University of Tübingen to M.K. and J.E. W.M. is a Royal Society University Research Fellow.
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Johnson, S., Franz, C., Kuhn, S. et al. Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses. Nat Neurosci 13, 45–52 (2010) doi:10.1038/nn.2456
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