Neuronal communication relies on the tightly controlled fusion of synaptic vesicles at nerve terminals, which results in the release of neurotransmitters with strict temporal and quantal precision. At rest, synaptic vesicle fusion is inhibited (Brunger et al., 2018). Action potential-mediated opening of voltage-gated Ca 2+ channels results in Ca 2+ influx into the nerve terminal, creating a Ca 2+ nanodomain that triggers the fusion of vesicles that are docked and primed at the plasma membrane, thereby evoking fast synchronous neurotransmitter release (Chanaday & Kavalali, 2018;Sudhof, 2013).Vesicles can additionally fuse asynchronously following evoked synchronous release and some spontaneous fusion of vesicles also occurs, though this is clamped (Chanaday & Kavalali, 2018).These processes are under exquisite regulatory control, preventing excessive neurotransmitter release and ensuring high-fidelity neuronal communication (Brunger et al., 2019;Rizo, 2018;; perturbation of this regulation can lead to a breakdown in neurotransmission.A range of presynaptic proteins are required to orchestrate these precision events. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, composed of the vesicular SNARE protein (v-SNARE) synaptobrevin and the target membrane SNARE proteins (t-SNAREs) syntaxin-1 and SNAP-25 (synaptosomal-associated protein-25), is the core fusion machinery that provides the energy required for fusion of synaptic vesicles with the plasma membrane (Weber et al., 1998). Several other key components regulate synaptic vesicle exocytosis in physiological environments (Brunger et al., 2019;Sudhof, 2014). SNARE complex assembly is orchestrated by Munc13 and Munc18, and further