Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes.

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

doi:10.1126/sciadv.abf3873

Abstract

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.

Highlights

The activity-dependent release of neurotransmitters at central synapses underpins brain function at the molecular, circuit, and behavioral level
We present evidence demonstrating that vesicle-associated membrane protein 4 (VAMP4) is a negative regulator of Pr and modulation of its abundance in Synaptic vesicle (SV) bestows differences in their fusogenicity
We demonstrate changes in both paired-pulse plasticity and the decay of synaptic facilitation during high-frequency stimulation in VAMP4 KO slices, consistent with Pr being the main determinant of presynaptic short-term plasticity [44, 48]

Summary

Introduction

The activity-dependent release of neurotransmitters at central synapses underpins brain function at the molecular, circuit, and behavioral level. Synaptic vesicle (SV) release probability (Pr), defined as the likelihood of an SV to fuse upon arrival of an action potential (AP), is one of the critical parameters in determining how synapses respond to changing patterns of activity. Pr is dynamically regulated by many interdependent factors, including presynaptic calcium homeostasis, the size of the readily releasable pool (RRP) of SVs, and SV heterogeneity [1]. SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor) proteins are essential components of the SV fusion machinery and key regulators of Pr. The SV R-SNARE synaptobrevin-2 (syb2) is indispensable for evoked synchronous neurotransmission [2]. SVs contain other R-SNARE proteins, including many endosomal SNAREs [3], that may confer differences in SV fusogenicity, providing an attractive mechanism to alter Pr via dynamic control of their copy number on SVs

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