Interneuronal exchange and functional integration of synaptobrevin via extracellular vesicles

Recent studies have investigated the composition and functional effects of extracellular vesicles (EVs) secreted by a variety of cell types. However, the mechanisms underlying the impact of these vesicles on neurotransmission remain unclear. Here, we isolated EVs secreted by rat and mouse hippocampal neurons and found that they contain synaptic-vesicle-associated proteins, in particular the vesicular SNARE (soluble N-ethylmaleimide-sensitive factor [NSF]-attachment protein receptor) synaptobrevin (also called VAMP). Using a combination of electrophysiology and live-fluorescence imaging, we demonstrate that this extracellular pool of synaptobrevins can rapidly integrate into the synaptic vesicle cycle of host neurons via a CD81-dependent process and selectively augment inhibitory neurotransmission as well as specifically rescue neurotransmission in synapses deficient in synaptobrevin. These findings uncover a novel means of interneuronal communication and functional coupling via exchange of vesicular SNAREs. •Neuronal extracellular vesicles (EVs) augment neurotransmitter release•Synaptobrevin-2 (syb2) is recruited to EVs via CD81•Syb2 from EVs is incorporated into functional recycling synaptic vesicles•EVs can rescue spontaneous neurotransmission in syb2 KO neurons Vilcaes et al. uncover a novel form of interneuronal communication using extracellular vesicles that allows the exchange of synaptic vesicle proteins, including synaptobrevin, via a CD81-dependent mechanism. Through this mechanism, neurons can modify the protein composition and signaling properties of other neurons.