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

Abstract

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, stressassociated 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.

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

“…These modifications resulted from the reduced binding of PP1 to the chromatin, and a reduced interaction between PP1 and JMJD2A, an H3K36-specific HDM, whereas the interaction between PP1 and lysine-specific demethylase 1 (LSD1), an H3K4-specific HDM, was unperturbed (171). Importantly, the findings that spatial learning induces H3 phosphorylation, together with H3 and H4 acetylation, were recently independently confirmed in both mice and rats (286).…”

Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2–MSK1–Elk-1 signaling

“…We postulated that after a FS challenge, activated GRs evoke epigenetic and gene expression changes and consolidation of behavioral immobility through a rapid interaction with the NMDA/ERK1/2/MSK1-signaling pathway (22). Activation of this signaling pathway would lead to serine-10 phosphorylation of histone H3 (by pMSK1) and acetylation of lysine-14, through recruitment of HATs, like CBP or p300.…”

“…Moreover, epigenetic, gene expression, and behavioral responses to forced swimming (FS) and novelty critically depend on GRmediated glucocorticoid action in dentate gyrus granule neurons (19)(20)(21). Thus, stress-induced behavioral responses involve activation of ERK MAPK and GR-mediated signaling in dentate neurons that converge and result in specific histone H3 modifications [i.e., serine-10 (S10) phosphorylation and lysine-14 (K14) acetylation (H3S10p-K14ac)] and activation of gene transcription (22). How these signaling pathways converge is presently unknown.…”

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…(iv) Facilitating effects of glucocorticoids are observed for memory consolidation, whereas detrimental effects are observed during information retrieval This general principle [8,12] was always observed in the reviewed studies focusing on glucocorticoid-glutamatergic interactions -in other words, the positive actions of glucocorticoids on cognition were generally related to memory consolidation [14,42,50,80,83] whereas impairing effects were linked to retrieval [34,38]). A key question to ask is whether these differential effects are due to a putative 'vulnerability' of these different cognitive processes [in either a positive (consolidation) or a negative (retrieval) manner] to stress or elevated glucocorticoids, or whether they are the consequence of serendipitous application of experimental designs in the respective studies with glucocorticoid timing and dosage (see above) being instead the key factors underlying the reported effects.…”

“…This in turn leads to the modulation of epigenomic mechanisms, particularly chromatin modifications, which affect gene transcription. This mechanism can explain facilitatory effects of glucocorticoids on memory consolidation [83]. (f) Glucocorticoids can activate transcription factors and signaling cascades, leading to a delayed increase in the probability of glutamate release.…”