Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing the formation and modulation of compartmentalized synaptic assemblies is unclear. Here, I used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (ePSD) scaffold proteins led to the formation of ePSD-like assemblies via phase separation. The reconstituted ePSD-like assemblies can cluster receptors, selectivel...[ Read more ]

Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing the formation and modulation of compartmentalized synaptic assemblies is unclear. Here, I used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (ePSD) scaffold proteins led to the formation of ePSD-like assemblies via phase separation. The reconstituted ePSD-like assemblies can cluster receptors, selectively concentrate enzymes, promote actin bundle formation, and expel inhibitory postsynaptic protein. Additionally, the condensed ePSD assemblies have features that are distinct from those in homogeneous solutions and fit for synaptic functions. Thus, I have built a molecular platform for understanding how neuronal synapses are formed and dynamically regulated.