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Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of  N -ethylmaleimide sensitive factor (NSF),  N -ethylmaleimide (NEM) or interfering peptides, prevent de-priming in  munc18-1/2SWAP  or  munc13-1 null  synapses, but not in  CAPS-1/2 null , another priming-deficient mutant. NEM rescues synaptic transmission in  munc13-1 null  and  munc18-1/2SWAP  synapses, in acute  munc13-1 null  slices and even partially in  munc13-1/2 double null  synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.

Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles