Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting

Recycling synaptic vesicles (SVs) transit through early endosomal sorting stations, which raises a fundamental question: are SVs sorted toward endolysosomal pathways? Here, we used snapin mutants as tools to assess how endolysosomal sorting and trafficking impact presynaptic activity in wild‐type and snapin −/− neurons. Snapin acts as a dynein adaptor that mediates the retrograde transport of late endosomes (LEs) and interacts with dysbindin, a subunit of the endosomal sorting complex BLOC‐1. Expressing dynein‐binding defective snapin mutants induced SV accumulation at presynaptic terminals, mimicking the snapin −/− phenotype. Conversely, over‐expressing snapin reduced SV pool size by enhancing SV trafficking to the endolysosomal pathway. Using a SV‐targeted Ca 2+ sensor, we demonstrate that snapin–dysbindin interaction regulates SV positional priming through BLOC‐1/AP‐3‐dependent sorting. Our study reveals a bipartite regulation of presynaptic activity by endolysosomal trafficking and sorting: LE transport regulates SV pool size, and BLOC‐1/AP‐3‐dependent sorting fine‐tunes the Ca 2+ sensitivity of SV release. Therefore, our study provides new mechanistic insights into the maintenance and regulation of SV pool size and synchronized SV fusion through snapin‐mediated LE trafficking and endosomal sorting. Synopsis Snapin‐mediated endolysosomal trafficking and sorting maintain synaptic vesicle pool size and fine‐tune the Ca 2+ sensitivity of evoked exocytosis. Dynein–snapin coupling driving late endosomal transport influences the total synaptic vesicle (SV) pool size by shuttling SV components along the endolysosomal pathway. Snapin‐mediated BLOC‐1/AP‐3‐dependent endosomal sorting determines SV composition and positional priming. By balancing these trafficking and sorting pathways, snapin coordinates the releasable pool size and Ca 2+ sensitivity of neurotransmitter release. Graphical Abstract Snapin‐mediated endolysosomal trafficking and sorting maintain synaptic vesicle pool size and fine‐tune the Ca 2+ sensitivity of evoked exocytosis.