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

• Published in: Nature communications Vol. 8; no. 1; p. 15915
• Main Authors: He, Enqi, Wierda, Keimpe, van Westen, Rhode, Broeke, Jurjen H., Toonen, Ruud F., Cornelisse, L. Niels, Verhage, Matthijs
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/548/2589; 631/378/87; 9/74; Animals; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Deficient mutant; Female; Humanities and Social Sciences; Mice; Mice, Inbred C57BL; multidisciplinary; Munc18 Proteins - genetics; Munc18 Proteins - metabolism; N-Ethylmaleimide; N-Ethylmaleimide-Sensitive Proteins - genetics; N-Ethylmaleimide-Sensitive Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Peptides; Priming; Retina; Science; Science (multidisciplinary); SNAP receptors; SNARE Proteins - genetics; SNARE Proteins - metabolism; Synapses; Synapses - metabolism; Synaptic Transmission; Synaptic vesicles; Synaptic Vesicles - genetics; Synaptic Vesicles - metabolism; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15915

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.
The molecular mechanism underlying the generation and maintenance of the readily releasable pool composed of primed synaptic vesicles is only partially known. Here the authors show that in mouse primary neurons, Munc13-1 and Munc18-1 stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.