Condensate biology of synaptic vesicle clusters

Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reli-able neurotransmitter release, synapses need to maintain an adequate pool of SVs at all times. Decades of research have established that SVs are clustered by synapsin 1, an abundant SV-associated phosphoprotein. The classical view postulates that SVs are crosslinked in a scaffold of protein-protein interactions between synapsins and their binding partners. Recent studies have shown that synapsins cluster SVs via liquid-liquid phase separation (LLPS), thus providing a new framework for the organization of the synapse. We discuss the evidence for phase separation of SVs, emphasizing emerging questions related to its regulation, specificity, and reversibility.

Automated summary

Neuronal communication relies on the exocytosis of neurotransmitters from clustered synaptic vesicles (SVs) at synapses. Synapsin 1, an abundant SV-associated phosphoprotein, has been established to be responsible for the clustering of SVs through protein-protein interactions. Recent studies have discovered that synapsins can cluster SVs through liquid-liquid phase separation (LLPS), presenting a new framework for understanding synaptic organization. This article discusses the evidence for SV phase separation and raises questions regarding its regulation, specificity, and reversibility.