Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity

Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD. [Display omitted] •SynGAP forms a coiled-coil trimer, and each binds to two molecules of PSD-95•SynGAP/PSD-95 complex undergoes liquid-liquid-phase separation•SynGAP/PSD-95 phase separation suggests a possible PSD formation mechanism•Phase-separation-mediated SynGAP PSD enrichment is correlated with synaptic activity The interaction between two major components of postsynaptic densities induces phase separation of the newly formed complex into liquid-like droplets, suggesting a mechanism for the formation and activity-dependent modulation of synaptic complexes.