Reddy-Alla, S., Böhme, M.A., Reynolds, E., Beis, C., Grasskamp, A.T., Mampell, M.M., Maglione, M., Jusyte, M., Rey, U., Babikir, H., McCarthy, A.W., Quentin, C., Matkovic, T., Bergeron, D.D., Mushtaq, Z., Göttfert, F., Owald, D., Mielke, T., Hell, S.W., Sigrist, S.J., Walter, A.M. (2017). Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission.  Neuron 95(6): 1350--1364.e12.

FBrf0236661

Research paper

Neural information processing depends on precisely timed, Ca(2+)-activated synaptic vesicle exocytosis from release sites within active zones (AZs), but molecular details are unknown. Here, we identify that the (M)Unc13-family member Unc13A generates release sites and show the physiological relevance of their restrictive AZ targeting. Super-resolution and intravital imaging of Drosophila neuromuscular junctions revealed that (unlike the other release factors Unc18 and Syntaxin-1A) Unc13A was stably and precisely positioned at AZs. Local Unc13A levels predicted single AZ activity. Different Unc13A portions selectively affected release site number, position, and functionality. An N-terminal fragment stably localized to AZs, displaced endogenous Unc13A, and reduced the number of release sites, while a C-terminal fragment generated excessive sites at atypical locations, resulting in reduced and delayed evoked transmission that displayed excessive facilitation. Thus, release site generation by the Unc13A C terminus and their specific AZ localization via the N terminus ensure efficient transmission and prevent ectopic, temporally imprecise release.