Synaptotagmin 7 negatively regulates synaptic vesicle release and replenishment in a dosage-dependent manner.

Synchronous neurotransmitter release is triggered by Ca binding to the synaptic vesicle protein Synaptotagmin 1, while asynchronous fusion and short-term facilitation is hypothesized to be mediated by plasma membrane-localized Synaptotagmin 7 (SYT7). We generated mutations in to determine if it plays a conserved role as the Ca sensor for these processes. Electrophysiology and quantal imaging revealed evoked release was elevated 2-fold. mutants also had a larger pool of readily-releasable vesicles, faster recovery following stimulation, and intact facilitation. double mutants displayed more release than mutants alone, indicating SYT7 does not mediate the residual asynchronous release remaining in the absence of SYT1. SYT7 localizes to an internal membrane tubular network within the peri-active zone, but does not enrich at active zones. These findings indicate the two Ca sensor model of SYT1 and SYT7 mediating all phases of neurotransmitter release and facilitation is not applicable at synapses.