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New paper from the Cousin lab published in Science Advances

The work uncovers how the non-canonical SNARE protein VAMP4 controls the probability of neurotransmitter release by coupling synaptic vesicle recycling to a major metabolic and signaling hub in neurons, the endolysosomal system.

Synaptic vesicle heterogeneity defines the probability of neurotransmitter release and its plastic control at central synapses. It is underpinned by differences in the molecular make-up of individual synaptic vesicles, which arise during synaptic vesicle recycling.

We discovered a new mechanism for diversification of synaptic vesicle composition and regulation of their fusion competence. We found that accumulation of the non-canonical vesicular SNARE, VAMP4, on synaptic vesicles, negatively affects their fusogenicity. This is mediated by the selective presynaptic clearance of VAMP4 by activity-dependent bulk endocytosis to endolysosomes during synaptic activity.

The rapid axonal turnover of VAMP4 enables its synaptic levels to change promptly in response to varying activity patterns or inhibition of the endolysosomal trafficking and function. Thus, VAMP4 is both a sensor and effector in a nested mechanism that mediates coordinated regulation of presynaptic release properties and cell-wide quality-control mechanisms to optimally support synaptic health and plasticity.

Several members of the Cousin lab contributed to this work: Primarily the project was conceived, executed and driven by Dr. Daniela Ivanova, with excellent support from Dr. Katharine Dobson, Dr. Elizabeth Davenport and Daniela Hacker.    

This work was funded by the Wellcome Trust and the RS McDonald Trust and was in collaboration with the groups of Matthias Trost (University of Newcastle) and Sila Ultanir (Crick Institute).  

Link to paper – https://advances.sciencemag.org/content/7/18/eabf3873

 

Well done all!