Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Abstract

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety-and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up-and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up-and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.S tress effects on higher brain regions, such as hippocampus, are known to involve actions of excitatory amino acids to induce structural and functional changes depending upon the type, intensity, and duration of the stressor (1). These differential responses, including determining susceptibility versus resilience to stress, contribute to the pathophysiology of debilitating stress-related disorders (2-5). The hippocampus is a brain region noted for its plasticity in response to stress and sensitivity to adrenal steroid hormones (6). Acute stress enhances synaptic plasticity that is associated with improved cognition and other adaptive functions whereas chronic stress produces opposite effects mediating, in the hippocampus, spine synapse turnover, dendritic shrinkage, impaired long-term potentiation (LTP), and suppression of adult neurogenesis in the dentate gyrus (DG) (1, 7). Importantly, neuroanatomical changes in response to repeated stress recover in young adult animals, based upon the restoration of dendritic length and branching and spine density (8). However, there are underlying changes that can be seen at the level of gene expression and epigenetic regulation that indicate that the brain is continually changing (9, 10). Epigenetic modifications, such as acetylation of histones, have also been involved in the consolidation of contextual memories that allow the brain to respond and adapt to changes in ...

Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

“…Although stress is well recognized as a key factor in precipitating a variety of disorders (29), including depression, the role of stress in altering the responsiveness to antidepressants is less known. Recently, we showed that stress opens windows of epigenetic plasticity in atrisk individuals (22) and these temporary slots of plasticity can be manipulated by LAC pharmacological intervention to increase resilience, whereby structural plasticity of the medial amygdala stellate neurons plays an important role (30). Here, our findings in endogenously depressed FSL subjected to an acute stress during LAC treatment show that an individual responsiveness to stress needs to be factored in toward the development of better therapeutics.…”

“…Here, we show that energy regulation via metabolic pathways is a target of LAC antidepressant treatment in the vDG, a limbic brain region important for depression and resilience to stress (22). While improving central deficits in the vDG and depressive-like behavior, LAC rapidly corrects systemic metabolic alterations in insulin and glucose levels associated with FSL.…”

“…1 B-D). A dynamic mGlu2 regulation has been shown recently in the vDG of chronically stressed mice, where windows of epigenetic plasticity that control behavior are seen in the immediate aftermath of stress with a glutamatergic hyperactivity of the vDG based on the continued down-regulation of the regulators of glutamate release, mGlu2 receptors, which normally inhibit neuronal glutamate release (21,22). Of note, nrFSL, which had lower mGlu2 in the vDG and high immobility at the FST compared with rFSL, also showed increased MR levels, in line with previous findings showing an MR-mediated down-regulation of mGlu2 that leads to glutamate overflow (8,23) and contributes to depression in mice prone to develop anxiety and depressive-like traits after stress.…”

Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice

“…A growing understanding of the relationship between stress-induced glucocorticoid elevation and glutamate neurotransmission has indicated that genetic differences in stress susceptibility could be modulated by the regulation of glutamate receptors (Nasca et al, 2015a, Nasca et al, 2015b). Additionally, a direct relationship between inflammation and the glutamate system has been demonstrated (Erhardt et al, 2013, Haroon et al, 2016).…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…Along this same line, a recent study used a combination of stressors to demonstrate that lasting epigenetic changes arising from a chronic stress paradigm may be briefly disrupted with subsequent short-term stress exposures (Nasca et al 2015). Chronic restraint stress decreased acetylation on lysine residue 27 of the metabotropic glutamate receptor 2 (Grm2), but exposure to a 2 h restraint stress transiently normalized this effect.…”