Modulating synaptic glutamate receptors by targeting network nodes of the postsynaptic density condensate

Biological condensates are assembled through phase separation and play critical roles in diverse cellular processes. Condensates in cells form percolated molecular networks via multi-valent interactions among biomolecules. How the network properties of a condensate are connected to its biological function is poorly understood. Using the neuronal postsynaptic density (PSD) condensate as a paradigm, we demonstrate thatbiological condensates can be bidirectionally modulated by strengthening or weakening different interaction nodes within the network. The clustering, mobility, and synaptic functions of AMPA receptors are exquisitely sensitive to alterations in the strength and complexity of the PSD condensate molecular network without changing the binding of the receptor to its direct downstream scaffold. Thus, biological condensates are complex systems with emergent network properties that are harnessed for cellular functions and in this case for synaptic plasticity.