Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes

The probability of synaptic vesicle (SV) fusion in response to an action potential, termed vesicular release probability (Pr), is a stochastic but tightly regulated process. SNARE proteins are the molecular executors of SV fusion and therefore, key modulators of Pr. The non-canonical SNARE VAMP4 is a cargo for activity-dependent bulk endocytosis (ADBE), a major SV retrieval mode operating during intense neuronal activity. Using optical imaging in primary neuronal cultures and slice electrophysiology from wild-type and VAMP4 knockout mice, we reveal that modulation of VAMP4 copy number on SVs is an important mechanism to regulate Pr. The control of VAMP4 copy number is determined by its clearance from axons via the endolysosomal system after its retrieval by ADBE. This activity-dependent regulatory mechanism enables synapses to 1) adapt their Pr dynamically to changing input and 2) couple regulation of synaptic strength to neuronal proteostasis.