Why is Most Neurotransmitter Release Synaptic

Abstract

Small-molecule neurotransmitter release is largely confined to synaptic active zones, but the spatially restrictive mechanism is unidentified. In this study, we investigate whether spatial restriction occurs during synaptic vesicle fusion with the plasma membrane or the priming stage where synaptic vesicles are attached to the plasma membrane. Calcium concentrations that activate low-affinity sensors like Syt-1 are achieved only at VGCCs that localize to active zones which may spatially restrict release. We hypothesize that spatial restriction can be overcome by high-affinity calcium sensors. Alternatively, restriction may occur during priming, which involves the formation of a complex of proteins located on synaptic vesicles and plasma membranes. A protein catalyzing this process, Munc13-1, is recruited and activated by the active zone protein RIM. This interaction may also cause release’s spatial confinement. Our cellular-imaging experiments utilizing a genetically encoded exocytosis sensor favors spatial restriction during priming. Additional work is necessary to resolve the question.