Fast vesicle replenishment allows indefatigable signalling at the first auditory synapse

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Abstract
Ribbon-type synapses in inner hair cells of the mammalian cochlea encode the complexity of auditory signals by fast and tonic release through fusion of neurotransmitter-containing vesicles. At any instant, only about 100 vesicles are tethered to the synaptic ribbon, and about 14 of these are docked to the plasma membrane1,2, constituting the readily releasable pool3. Although this pool contains about the same number of vesicles as that of conventional synapses4,5, ribbon release sites operate at rates of about two orders of magnitude higher3,6,7 and with submillisecond precision8,9,10,11. How these sites replenish their vesicles so efficiently remains unclear3,12,13. We show here, using two-photon imaging of single release sites in the intact cochlea, that preformed vesicles derived from cytoplasmic vesicle-generating compartments14 participate in fast release and replenishment. Vesicles were released at a maximal initial rate of 3 per millisecond during a depolarizing pulse, and were replenished at a rate of 1.9 per millisecond. We propose that such rapid resupply of vesicles enables temporally precise and sustained release rates. This may explain how the first auditory synapse can encode with indefatigable precision without having to rely on the slow, local endocytic vesicle cycle7.