Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission
2017
Authors: Reddy-Alla S, Böhme MA, Reynolds E, Beis C, Grasskamp AT, Mampell MM, Maglione M, Jusyte M, Rey U, Babikir H, McCarthy AW, Quentin C, Matkovic T, Bergeron DD, Mushtaq Z, Göttfert F, Owald D, Mielke T, Hell SW, Sigrist SJ, Walter AM
CellNetworks People: Hell Stefan
Journal: Neuron. 2017 Sep 13;95(6):1350-1364.e12. doi: 10.1016/j.neuron.2017.08.016

Neural information processing depends on precisely timed, Ca2+-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.