title: 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.
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@rockefeller.edu cnasca@rockefeller.edu.
authors.forename: Carla
authors.initials: C
authors.lastname: Nasca
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Danielle
authors.initials: D
authors.lastname: Zelli
authors.affiliation: Center for Clinical & Translational Science, The Rockefeller University, New York, NY 10065;
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bigio
authors.affiliation: Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute, 00143 Rome, Italy;
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, 00135 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Scaccianoce
authors.affiliation: Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute, 00143 Rome, Italy; Department of Physiology and Pharmacology, Sapienza University, 00135 Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@rockefeller.edu cnasca@rockefeller.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology; D003863:Depression / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018698:Glutamic Acid; D006657:Histones; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C409466:NR1 NMDA receptor; C108822:metabotropic glutamate receptor 2
keywords: BDNF; H3K27; NMDA; mGlu2; resilience