Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

Accumulating evidence indicates the key role of alpha-calcium/calmodulin-dependent protein kinase II (alpha CaMKII) in synaptic plasticity and learning, but it remains unclear how this kinase participates in the processing of memory extinction. Here, we investigated the mechanism by which alpha CaMKII may mediate extinction by using heterozygous knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of this kinase (alpha CaMKIIT286A+/-). Remarkably, partial reduction of alpha CaMKII function due to the T286A(+/-) mutation prevented the development of extinction without interfering with initial hippocampus-dependent memory formation as assessed by contextual fear conditioning and the Morris water maze. It is hypothesized that the mechanism of extinction may differ depending on the interval at which extinction training is started, being more akin to new learning at longer intervals and unlearning or erasure at shorter intervals. Consistent with this hypothesis, we found that extinction conducted 24 h, but not 15 min, after contextual fear training showed spontaneous recovery (reappearance of extinguished freezing responses) 21 d following the extinction, representing behavioral evidence for new learning and unlearning mechanisms underlying extinction 24 h and 15 min post-training, respectively. Importantly, the alpha CaMKIIT286A+/- mutation blocked new learning of contextual fear memory extinction, whereas it did not interfere with unlearning processes. Our results demonstrate a genetic dissociation of new learning and unlearning mechanisms of extinction, and suggest that alpha CaMKII is responsible for extinguishing memories specifically through new learning mechanisms.