Plasticity of central synaptic transmission has been considered as the mechanism of learning and memory. Its disruption causes neuropsychiatric and neurocognitive disorders. The molecular mechanism of synaptic plasticity has been the center of research since its discovery. I have been particularly interested in the postsynaptic signaling process regulating synaptic surface receptor and found that activity-dependent trafficking of various receptor and intracellular components during synaptic plasticity. This is triggered by the raise in intracellular Ca²⁺ concentration, which in turn triggers various signaling cascades. Among them, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) has been considered pivotal signaling molecule in the synaptic plasticity. However, its characteristic dodecameric structure and abundance at the synapse have been mystery. I found that CaMKII can indeed undergo liquid-liquid phase separation in a manner dependent on Ca²⁺/calmodulin- with its substrate proteins and cross-link them together. This modulates the distribution of synaptic surface receptors and define their nanodomains. In this way, Ca²⁺-dependent liquid-liquid phase separation of CaMKII and other synaptic proteins is a mechanism to modulate synaptic transmission persistently during synaptic plasticity.