Role of ERK2 dimerization in synaptic plasticity and memory

Extensive research has focused on extracellular-signal regulated kinase 1/2 (ERK) phosphorylation in different memory and plasticity models. However, the precise mechanism by which ERK activity leads to memory stabilization and restabilization remains largely elusive, and little is known about the role of ERK 1/2 dimerization in those processes. ERK dimerization is critical for the binding and activation of extranuclear targets, some of which have been strongly associated with these processes. Here we report for the first time that ERK2 dimerization occurs in the context of the rodent nervous system and plays a critical role in plasticity and memory processes. ERK2 dimerization was blocked by DEL-22379 (DEL), a recently developed specific ERK dimerization inhibitor in mice hippocampus in vivo. Moreover, DEL impaired high frequency stimulation-induced long-term potentiation in acute hippocampal slices. However, inhibitory avoidance (IA) memory reactivation induced a significant decrease of ERK2 dimerization in hippocampi from weak IA-trained mice. Noteworthily, intrahippocampal infusion of the inhibitor after memory reactivation had a surprising bidirectional effect: while it blocked reconsolidation of a strong IA memory, the opposite effect was observed on reconsolidation of a weak IA memory, resulting in its enhancement. Although more research is needed, these initial findings suggest a relevant role of ERK dimerization in plasticity and memory.