Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes

Daniela Ivanova, Katharine Dobson, Akshada Gajbhiye, Elizabeth Davenport, Daniela Hacker, Sila K Ultanir, Mattias Trost, Michael A Cousin

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Synaptic vesicle (SV) release probability (Pr), determines the steady state and plastic control of neurotransmitter release. However, how diversity in SV composition arises and regulates the Pr of individual SVs is not understood. We found that modulation of the copy number of the noncanonical vesicular SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor), vesicle-associated membrane protein 4 (VAMP4), on SVs is key for regulating Pr. Mechanistically, this is underpinned by its reduced ability to form an efficient SNARE complex with canonical plasma membrane SNAREs. VAMP4 has unusually high synaptic turnover and is selectively sorted to endolysosomes during activity-dependent bulk endocytosis. Disruption of endolysosomal trafficking and function markedly increased the abundance of VAMP4 in the SV pool and inhibited SV fusion. Together, our results unravel a new mechanism for generating SV heterogeneity and control of Pr through coupling of SV recycling to a major clearing system that regulates protein homeostasis.
Original languageEnglish
Article numbereabf3873
Number of pages21
JournalScience Advances
Early online date30 Apr 2021
Publication statusE-pub ahead of print - 30 Apr 2021


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