Regulation of synaptic nanodomain by liquid–liquid phase separation: A novel mechanism of synaptic plasticity

Advances in microscopy techniques have revealed the details of synaptic nanodomains as defined by the segregation of specific molecules on or beneath both presynaptic and postsynaptic membranes. However, it is yet to be clarified how such segregation is accomplished without demarcating membrane and how nanodomains respond to the neuronal activity. It was recently discovered that proteins at the synapse undergo liquid–liquid phase separation (LLPS), which not only contributes to the accumulation of synaptic proteins but also to further segregating the proteins into subdomains by forming phase-in-phase structures. More specifically, CaMKII, a postsynaptic multifunctional kinase that serves as a signaling molecule, acts as a synaptic cross-linker which segregates certain molecules through LLPS in a manner triggered by Ca²⁺. Nanodomain formation contributes to the establishment of trans-synaptic nanocolumns, which may be involved in the optimization of spatial arrangement of the transmitter release site and receptor, thereby serving as a new mechanism of synaptic plasticity.