Antidepressant epigenetic action

Flight, Monica Hoyos

doi:10.1038/nrn3466

Cited by 15 publications

(23 citation statements)

References 1 publication

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“…Because excessive glutamatergic activity is a key mediator of stress-induced changes in hippocampal morphology and function (1), we evaluated the effects of stress upon key glutamate genes based on the type, intensity, and duration of the stress. We first evaluated the impact of prolonged 21 d of chronic-restraint stress (CRS) on the presynaptic mGlu2 receptor and on the obligatory subunit NR1 of the NMDA receptor, targets for novel rapidly acting antidepressants (18)(19)(20)23). As expected from previous work (24), 21-d CRS, which leads to dendritic remodeling in the CA3 hippocampus (6), resulted in a significant increase in adrenal-to-body weight ratio compared with nonstressed mice (Fig.…”

Section: Differential Responses Of the Hippocampus To Novel And Familiarmentioning

confidence: 83%

“…Because P300 is a regulator of acetylation of histone-3-lysine-27-acetylation (H3K27ac), an epigenetic marker that has been correlated with transcriptional activation (30) and a consistent marker of antidepressant action (18)(19)(20), we performed ChIP for the H3K27ac bound to the promoter of the Grm2 gene, which encodes for mGlu2 receptors. In keeping with the finding that many epigenetic markers are rapidly regulated and transient (30), we found that the CRSinduced decrease in H3K27ac in the Grm2 promoter was rapidly reversed 2 h after ARS in CRS mice and was once again downregulated 24 h after ARS in CRS mice (Fig.…”

Section: P300 Regulates the Mglu2-driven Window Of Plasticity Opened mentioning

confidence: 99%

“…Because the brain is continually changing its gene expression with experience (10), we wanted to know how a history of stress alters-behaviorally, physiologically, and epigenetically-the responsivity to subsequent life stressful events, conferring a differential susceptibility to psychopathologies. We investigated in depth histone-3-lysine-27-acetylation (H3K27ac), a consistent biomarker of mood-related behaviors and antidepressant action (18)(19)(20). We demonstrate that a history of chronic stress alters the response to familiar (known) and unfamiliar (unknown) stressors, such that familiar acute restraint stress (ARS) and a novel acute forced swim stress (AFS) have differential effects upon the putative presynaptic mGlu2 and postsynaptic NR1/ NMDA receptors in the hippocampus of naive and chronically stressed mice.…”

Section: Significancementioning

confidence: 99%

“…Animal models have shown that chronic stress effects on dendritic remodeling are blocked by blocking NMDA receptors (1,16) and that adrenalectomy attenuates the acute stress-induced elevations of extracellular glutamate levels in the hippocampus (1,17). More recently, presynaptic type 2 metabotropic glutamate (mGlu2) receptor, an inhibitor of synaptic glutamate release, has been identified as a marker of stress susceptibility (2) and as a target for novel rapidly acting antidepressants (18)(19)(20), such as acetyl-L-carnitine (LAC). LAC rapidly up-regulated mGlu2 in the hippocampus, along with correcting depressive-like behaviors (18)(19)(20).…”

mentioning

confidence: 99%

“…More recently, presynaptic type 2 metabotropic glutamate (mGlu2) receptor, an inhibitor of synaptic glutamate release, has been identified as a marker of stress susceptibility (2) and as a target for novel rapidly acting antidepressants (18)(19)(20), such as acetyl-L-carnitine (LAC). LAC rapidly up-regulated mGlu2 in the hippocampus, along with correcting depressive-like behaviors (18)(19)(20). LAC also elevated BDNF levels in a genetic animal model of depressive-like behavior (18).…”

mentioning

confidence: 99%

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

Nasca

Zelli

Bigio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

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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 ...

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Section: Differential Responses Of the Hippocampus To Novel And Familiarmentioning

confidence: 83%

Section: P300 Regulates the Mglu2-driven Window Of Plasticity Opened mentioning

confidence: 99%