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Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes

Lookup NU author(s): Dr Akshada Gajbhiye, Professor Matthias TrostORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).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.

Publication metadata

Author(s): Ivanova D, Dobson KL, Gajbhiye A, Davenport EC, Hacker D, Ultanir SK, Trost M, Cousin MA

Publication type: Article

Publication status: Published

Journal: Science Advances

Year: 2021

Volume: 7

Issue: 18

Print publication date: 30/04/2021

Online publication date: 30/04/2021

Acceptance date: 11/03/2021

Date deposited: 10/06/2021

ISSN (electronic): 2375-2548

Publisher: American Association for the Advancement of Science


DOI: 10.1126/sciadv.abf3873


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