Phase separation-mediated actin bundling by the postsynaptic density condensates

Abstract

AbstractThe volume and the electric strength of an excitatory synapse is near linearly correlated with the area of its postsynaptic density (PSD). Extensive research in the past have revealed that the PSD assembly directly communicates with actin cytoskeleton in the spine to coordinate activity-induced spine volume enlargement as well as long-term stable spine structure maintenance. However, the molecular mechanism underlying the communication between the PSD assembly and spine actin cytoskeleton is poorly understood. In this study, we discover thatin vitroreconstituted PSD condensates can promote actin polymerization and filamentous actin bundling without help of any actin regulatory proteins. The Homer scaffold within the PSD condensates and a positively charged actin binding surface of the Homer EVH1 domain are essential for the PSD condensate-induced actin bundle formationin vitroand for spine growth in neurons. Homer-induced actin bundling can only occur when Homer forms condensates with other PSD scaffold proteins such as Shank and SAPAP. The PSD-induced actin bundle formation is sensitively regulated by CaMKII or by the product of the immediate early geneHomer1a. Thus, the communication between PSD and spine cytoskeleton may be modulated by targeting the phase separation of the PSD condensates.