Single-molecule imaging reveals activity-dependent regulation of Camk2a mRNAs at dendritic spines

Postsynaptic calcium/calmodulin-dependent protein kinase type II (CaMKII) integrates fleeting Ca ²⁺ transients into long-term synaptic potentiation (LTP). A persistent presence of CaMKIIα at dendritic spines during the maintenance of LTP facilitates the prolongation of synaptic transmission. Yet, it remains unclear how the perpetuation of CaMKIIα, despite protein turnover, is achieved at dendritic spines. By visualizing endogenous Camk2a mRNAs at single molecule resolution using a newly developed mouse model, we identified a rapid activity-dependent localization of mRNAs to stimulated spines near the postsynaptic density (PSD) of hippocampal neurons. This spine localization was conferred by cis -acting regulatory elements termed cytoplasmic polyadenylation elements (CPEs) in Camk2a mRNA. Spine-localized Camk2a underwent on-site translation, which persisted for extended periods. These findings uncovered a novel local regulation of Camk2a mRNA, which serves to supply dendritic spines with a steady pool of highly concentrated CaMKIIα for maintaining long-lasting synaptic plasticity.