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

Enqi He, Keimpe Wierda, Rhode van Westen, Jurjen H. Broeke, Ruud F. Toonen, L. Niels Cornelisse and Matthijs Verhage ()
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Enqi He: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU)
Keimpe Wierda: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU)
Rhode van Westen: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU Medical Center
Jurjen H. Broeke: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU Medical Center
Ruud F. Toonen: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU)
L. Niels Cornelisse: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU Medical Center
Matthijs Verhage: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU)

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15915

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