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40 reviewsSUMMARYCells contain numerous types of membraneless organelles or biological condensates formed via phase separation. Cellular biological condensates have broad material properties ranging from Newtonian fluids toelastic solids. How the material property of a biological condensate is regulated for cellular functions is poorlyunderstood. Here, we discovered that, like native postsynaptic densities (PSDs), the reconstituted PSDcondensate forms a soft glass material without signs of irreversible amyloid structure formation. Suchglass-like PSD condensate formation is based on percolation of the PSD protein network via specific andmultivalent interactions among scaffold proteins. Disruption of Shank3 SAM domain-mediated oligomerization, one type of SHANK3 mutation observed in Phelan-McDermid syndrome patients, softened the PSDcondensate by weakening its network percolation, impaired synaptic transmission and plasticity, and causedautistic-like behavior in mice. Thus, our study suggests that the material properties of the PSD condensateare critical for learning and memory mediated by neuronal synapses.
