CaMKII monomers are sufficient for GluN2B binding, co-condensation, and synaptic potentiation.

Cognitive functions require synaptic plasticity, specifically long-term potentiation (LTP). LTP is thought to require Ca2+/CaM-dependent protein kinase II (CaMKII) binding to the NMDA-type glutamate receptor subunit GluN2B, but this poses a conundrum: truncated CaMKII monomers (without the hub domain that forms 12meric holoenzymes) fail to bind GluN2B within cells but still potentiate synapses when made constitutively active. We hypothesized that CaMKII monomer binding to GluN2B has just eluded detection. Instead, even though full-length CaMKII monomers (with hub-domain mutations) were found to indeed bind and even form condensates with GluN2B, truncated monomers were not. Nonetheless, truncated monomers still potentiated synapses, even in neurons with GluN2B mutations that ablate CaMKII binding. However, potentiation occurred only with monomers that were made Ca2+-independent by artificial phosphatase-resistant thio-autophosphorylation, not by regular autophosphorylation of T286. These findings support that CaMKII binding to GluN2B is required during physiological LTP induction because it generates the phosphatase-resistant autonomous activity that mediates LTP expression.