CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation

Ca2+/calmodulin-dependent kinase II alpha (CaMKII alpha) is essential for synaptic plasticity and learning by decoding synaptic Ca2+ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKII alpha's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKII alpha. We demonstrate that Shank3 and GluN2B, via combined actions of Ca2+ and phosphatases, reciprocally bind to CaMKII alpha. Under basal condition, CaMKII alpha is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca2+ concentration induces GluN2B-mediated recruitment of active CaMKII alpha and formation of the CaMKII alpha/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca2+ removal. Protein phosphatases control the Ca2+-dependent shuttling of CaMKII alpha between the two PSD subcompartments and PSD condensate formation. Activation of CaMKII alpha further enlarges the PSD assembly and induces structural LTP. Thus, Ca2+-induced and phosphatase-checked shuttling of CaMKII alpha between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.