CaMKII-Mediated Phase Separation as a Driver of Synaptic Maturation

Abstract

Synaptic maturation coordinates structural spine remodeling with the nanoscale organization of neurotransmitter receptors. While Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a well-known structural and enzymatic scaffold at excitatory synapses, the mechanism linking its developmental expression to the maturation of the postsynaptic density (PSD) has remained unclear. Kuo et al. (2025) demonstrate that the developmental increase in CaMKII levels triggers liquid–liquid phase separation (LLPS) with the GluN2B subunit of NMDA receptors. This phase transition is necessary and sufficient to drive spine enlargement and the segregation of AMPA and NMDA receptor nanodomains. By identifying LLPS as the physical driver of this reorganization, the author provides a unified framework for how synapses acquire their mature architecture and highlights open questions about the functional impact of receptor nanodomains.