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Summary: SNARE-mediated synaptic vesicle (SV) fusion is controlled by multiple regulatory proteins that determine neurotransmitter release efficiency. Complexins are essential SNARE regulators whose mode of action is unclear, as available evidence indicates positive SV fusion facilitation and negative “fusion clamp”-like activities, with the latter occurring only in certain contexts. Because these contradictory findings likely originate in part from different experimental perturbation strategies, we attempted to resolve them by examining a conditional complexin-knockout mouse line as the most stringent genetic perturbation model available. We found that acute complexin loss after synaptogenesis in autaptic and mass-cultured hippocampal neurons reduces SV fusion probability and thus abates the rates of spontaneous, synchronous, asynchronous, and delayed transmitter release but does not affect SV priming or cause “unclamping” of spontaneous SV fusion. Thus, complexins act as facilitators of SV fusion but are dispensable for “fusion clamping” in mammalian forebrain neurons. : Complexins are thought to either promote synaptic vesicle fusion or act as “fusion clamps.” López-Murcia et al. show that acute genetic complexin deletion reduces the rates of all forms of transmitter release in forebrain neurons without affecting vesicle priming. Thus, complexins are facilitators of vesicle fusion and dispensable for “fusion clamping.” Keywords: complexin, synaptic vesicle, fusion, hippocampal neurons, synaptic transmission