Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity Contributed by Bruce S. McEwen, October 20, 2015 (sent for review August 12, 2015; reviewed by Bita Moghaddam and Johannes M. H. M. Reul) http://www.pnas.org/content/112/48/14960
Chronic stress alters the hippocampal responses to familiar and novel stressors, behaviorally, physiologically, and epigenetically. In the aftermath of chronic stress in WT mice and in mice with a BDNF loss-of-function allele without any applied stress, there is a window of plasticity that allows familiar and novel experiences to alter anxiety- and depressive-like behaviors, reflected also in electrophysiological changes in the dentate gyrus (DG) in vitro. A consistent biomarker of mood-related behaviors in DG is reduced type 2 metabotropic glutamate (mGlu2), which regulates the release of glutamate. Within this window, familiar stress rapidly and epigenetically up-regulates mGlu2 by a P300-driven histone H3 lysine 27 acetylation and improves mood behaviors. This transient epigenetic plasticity may be useful for treatment of stress-related disorders where dysregulaton of glutamate is involved.
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.