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

Zeng, M. et al. Cell, 166(5), 1163-1175 (25 August 2016).

Review by Rachel Brunetti

Postsynaptic densities (PSDs) are semi-enclosed, protein-rich compartments below the membrane of postsynaptic neurons. Zeng et al. seek to better understand the fundamentals of PSDs—namely how they form, how they persist without a membrane, and how they are modified by neuronal excitation. The group focuses on two key PSD proteins, PSD-95, a known PSD scaffolding protein, and SynGAP, a GTPase activating protein downstream of PSD-95. Through a structural study the group finds that PSD-95 has a secondary binding site responsible for the high binding affinity of SynGAP, which allows it to outcompete other PSD proteins. They also show that SynGAP forms a trimeric coiled-coil, which, along with SynGAP-induced dimerization of PSD-95, mediates a 3:2 stoichiometric ratio. The multivalency of this complex supports the group’s major finding that purified PSD-95 and SynGAP coalescence into liquid droplets. They verify this occurs in live cells and take steps towards understanding it in a neuron model. In neurons SynGAP foci form, and the foci of mutants with lower PSD-95/SynGAP affinity prove less stable with cell stimulation. This suggests a hyper-excitable phenotype that may correspond to intellectual disorders. While this paper makes broader claims than it can justify, it makes a novel discovery in PSD fundamentals while managing to span multiple length scales. These findings promote a new way of thinking about PSD biology.