Phase separation in the multi-compartment organization of synapses

A neuronal synapse is formed by juxtaposition of a transmitter releasing presynaptic bouton of one neuron with a transmitter receiving postsynaptic compartment such as a spine protrusion of another neuron. Each presynaptic bouton and postsynaptic spine, though very small in their volumes already, are further compartmentalized to micro-/nano-domains with distinct molecular organizations and synaptic functions. This review summarizes studies in recent years demonstrating that multivalent protein–protein interaction-induced phase separation underlies formation and coexistence of multiple distinct molecular condensates within tiny synapses. In post-synapses where synaptic compartmentalization via phase separation was first demonstrated, phase separation allows clustering of transmitter receptors into distinct nanodomains and renders postsynaptic densities to be regulated by synaptic stimulation signals for plasticity. In pre-synapses, such phase separation-mediated synaptic condensates formation allows SVs to be stored as distinct pools and directly transported for activity-induced transmitter release.