The forced swimming‐induced behavioural immobility response involves histone H3 phospho‐acetylation and c‐Fos induction in dentate gyrus granule neurons via activation of the N‐methyl‐d‐aspartate/extracellular signal‐regulated kinase/mitogen‐ and stress‐activated kinase signalling pathway

Abstract

The hippocampus is involved in learning and memory. Previously, we have shown that the acquisition of the behavioural immobility response after a forced swim experience is associated with chromatin modifications and transcriptional induction in dentate gyrus granule neurons. Given that both N-methyl-D-aspartate (NMDA) receptors and the extracellular signal-regulated kinases (ERK) 1/2 signalling pathway are involved in neuroplasticity processes underlying learning and memory, we investigated in rats and mice whether these signalling pathways regulate chromatin modifications and transcriptional events participating in the acquisition of the immobility response. We found that: (i) forced swimming evoked a transient increase in the number of phospho-acetylated histone H3-positive [P(Ser10)-Ac(Lys14)-H3(+)] neurons specifically in the middle and superficial aspects of the dentate gyrus granule cell layer; (ii) antagonism of NMDA receptors and inhibition of ERK1/2 signalling blocked forced swimming-induced histone H3 phospho-acetylation and the acquisition of the behavioural immobility response; (iii) double knockout (DKO) of the histone H3 kinase mitogen- and stress-activated kinases (MSK) 1/2 in mice completely abolished the forced swimming-induced increases in histone H3 phospho-acetylation and c-Fos induction in dentate granule neurons and the behavioural immobility response; (iv) blocking mineralocorticoid receptors, known not to be involved in behavioural immobility in the forced swim test, did not affect forced swimming-evoked histone H3 phospho-acetylation in dentate neurons; and (v) the pharmacological manipulations and gene deletions did not affect behaviour in the initial forced swim test. We conclude that the forced swimming-induced behavioural immobility response requires histone H3 phospho-acetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway.

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

“…For instance, antidepressants are able to modulate glutamatergic neurotransmission (56), which is capable of activating intracellular mechanisms that culminate with the modulation of the epigenetic machinery (57,58). In fact, it was reported that exposure to stressful events and consequent increased release of glucocorticoids and glutamate (and NMDA activation) can result in the phosphorylation of ERK1/2 which form a complex with GR and induce transcription factors that culminate with the modulation of the epigenetic machinery (57,58). Therefore, antidepressants could ultimately target DNMT activity acutely by modulating glutamate-induced levels upon stress exposure.…”

Regulation of hippocampal H3 histone methylation by acute and chronic stress

“…Chronic social defeat stress has been shown to alter acetylation and methylation of histones on the promoter regions of a number of genes in the nucleus accumbens (38,40) and anti-depressant treatment in this model has been shown to reverse some of these effects. Acute stress has been shown to have an impact on histone acetylation and phosphorylation levels in the hippocampal formation (15,41,42). It, therefore, seems that chromatin remodeling in the brain is likely to play a significant role in normal and pathogenic responses to stress and in the treatment of stressrelated diseases.…”

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…These circumstances foster both rapid and delayed (protein-synthesisdependent) synaptic delivery of AMPAR and/or NMDAR subunits [39,40,42,51]. A subsequent and/or additional pathway involves NMDAR-triggering of signaling cascades leading to (epi)genomic changes in gene transcription [14,[73][74][75]80], with at least one of these targets leading to increased probability of glutamate release [80]. In general, rapid effects are mediated by membrane-bound MRs or GRs, whereas delayed genomic effects are mediated by nuclear-localized GRs.…”

“…Specifically, evidence has been presented that glucocorticoid-induced enhancement of memory consolidation (as assessed in a forced swim test) took place through the activation of NMDARs and the downstream mitogen-activated protein kinase (MAPK) pathway, including activation of ERK (extracellular signal-regulated kinase)/MSK (mitogen and stress-activated protein kinase) and transcription factor Elk-1 in the dentate gyrus of the hippocampus [73][74][75]. Activation of this pathway was demonstrated to result in epigenetic changes including enhanced histone acetylation [73][74][75]. These epigenetic mechanisms were only efficient in the presence of activated GRs and they acted in synergy with NMDAR activation [74] (Figure 1e).…”