Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation

We make strong memories of significant events in our lives which may serve to increase our resilience and adaptation capacity to deal with future challenges. It is well established that the neurotransmitter glutamate and the ERK MAPK intracellular signaling pathway play a principal role in memory formation. In addition, stress-associated hormones like glucocorticoids released during such events are known to strengthen formation of memories. But, how do these hormones work? Do they interact with the ERK MAPK pathway or otherwise? What are the more distal, epigenomic effects? We discovered in rats and mice that confrontation with a psychological challenge (e.g., forced swimming, Morris water maze) would lead, through NMDA-ERK signaling, to MSK1 and Elk-1 activation in dentate gyrus neurons (a part of the hippocampus involved in encoding of memories) resulting in histone H3 S10-phosphorylation and K14-acetylation, H4 hyper-acetylation, gene induction and formation of memories of the event. Moreover, glucocorticoid hormones via the glucocorticoid receptor (GR) greatly facilitated the epigenomic mechanisms and cognitive performance. Therefore, we propose that formation of enduring memories of significant events requires an interaction of GRs with the NMDA/ERK/MSK1/Elk-1 signaling pathways to allow an optimal epigenomic activation pattern in dentate gyrus neurons to accommodate their altered neurophysiological function.