Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

Abstract

During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability ofrelease-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregu-lated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV primingprotein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines withpoint mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishingCa2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pooldepletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid bindinghas the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR,reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotrans-mission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand