Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses

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Abstract
Mammalian cochlea inner hair cells (IHCs) can code a continuous grading of sound intensities. This is because neurotransmitter release at mature sensory ribbon synapses is linearly dependent on calcium influx, which has the effect of broadening the cells' dynamic range. Immature IHC neurotransmitter release is quite different. Here, the authors show that a switch from syanptogamin I and II to synaptogamin IV underlies this developmental change. 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.