Neuronal Synapses: Microscale Signal Processing Machineries Formed by Phase Separation?

The organization principles underlying non-membrane-bound organelles have started to unravel in the past 10 years. A new biophysical model known as biomolecular condensates has been proposed to explain many aspects of membraneless organelle assembly and regulation. Neurons are extremely complex, and each neuron can contain tens of thousands of synapses, building an extensive neuronal circuit. Intriguingly, neuronal synapses are characterized by specialized compartmentalization, where highly enriched supramolecular complexes are semi-membrane-enclosed into submicrometer-sized signal processing compartments. Recent findings have demonstrated that this postsynaptic density may be driven by phase separation, and an increasing number of studies of membraneless compartments have shed light on the important molecular features shared by these organelles. Here, we discuss the unique morphology and composition of synapses and consider how synaptic assembly might be driven by phase separation. Understanding the molecular behavior of this semi-membrane-bound compartment could ultimately help to explain the mechanistic details underlying synaptic transmission and plasticity, as well as the numerous brain disorders caused by synaptic defects.