Reconstituted Postsynaptic Density as a Molecular Platform for Understanding Synapse Formation and Plasticity

• Published in: Cell 2018-08, Vol.174 (5), p.1172-1187.e16
• Main Authors: Zeng, Menglong, Chen, Xudong, Guan, Dongshi, Xu, Jia, Wu, Haowei, Tong, Penger, Zhang, Mingjie
• Format: Article
• Language: English
• Subjects: Animals; biochemical reconstitution; biomolecular condensates; Brain - physiology; Disks Large Homolog 4 Protein - physiology; Hippocampus - physiology; Light; membraneless organelle; Mice; Microscopy, Confocal; Neurogenesis; Neuronal Plasticity; Neurons - physiology; phase separation; Post-Synaptic Density; postsynaptic density; scaffold proteins; Scattering, Radiation; Signal Transduction; synapse formation; Synapses - physiology; synaptic signaling; Synaptic Transmission
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.06.047

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 formation and modulation of compartmentalized synaptic assemblies is unclear. Here, we 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 (PSD) scaffold proteins led to formation of PSD-like assemblies via phase separation. The reconstituted PSD-like assemblies can cluster receptors, selectively concentrate enzymes, promote actin bundle formation, and expel inhibitory postsynaptic proteins. Additionally, the condensed phase PSD assemblies have features that are distinct from those in homogeneous solutions and fit for synaptic functions. Thus, we have built a molecular platform for understanding how neuronal synapses are formed and dynamically regulated. [Display omitted] •Biochemical reconstitution reveals PSD assembly formation via phase separation•The ePSD condensates cluster NMDA receptor and promote actin bundle formation•The ePSD condensates selectively enrich SynGAP and actively exclude gephyrin•The ePSD condensates can be modulated by activity-dependent protein modifications Phase transition-mediated formation of excitatory postsynaptic density condensates revealed by biochemical reconstitutions.