Hippocampal ERK2 dimerization is critical for memory reconsolidation and synaptic plasticity

Extensive research has focused on extracellular-signal regulated kinase (ERK) 1/2 phosphorylation across various memory and plasticity models. However, the precise mechanism linking ERK activity to memory stabilization and restabilization are still poorly understood, and the role of ERK1/2 dimerization remains unexplored. ERK dimerization is essential for the binding and activation of cytoplasmic targets, many of which have been strongly implicated in memory and plasticity. In this work, we studied the role of ERK2 dimerization in memory and synaptic plasticity through several experimental approaches. We found that reactivation of a weak inhibitory avoidance (wIA) memory led to a significant reduction in hippocampal ERK2 dimerization. Furthermore, intrahippocampal infusion of DEL-22379 (DEL), an ERK dimerization inhibitor, following memory reactivation had a bidirectional effect: it blocked the reconsolidation of a strong inhibitory avoidance (sIA) memory, but enhanced the reconsolidation of a wIA memory. Moreover, DEL administration blocked hippocampal ERK2 dimerization in vivo and impaired high-frequency stimulation-induced long-term potentiation (LTP) in hippocampal slices. These findings demonstrate for the first time that ERK2 dimerization occurs in the intact rodent nervous system and plays a pivotal role in plasticity and memory. While further research is needed, this study highlights the relevance of ERK dimerization in these processes.