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

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 interact...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-12, Vol.112 (48), p.14960-14965
Main Authors: Nasca, Carla, Zelli, Danielle, Bigio, Benedetta, Piccinin, Sonia, Scaccianoce, Sergio, Nisticò, Robert, McEwen, Bruce S.
Format: Article
Language:English
Subjects:
Amino acids
Animals
Anxiety - genetics
Anxiety - metabolism
Anxiety - pathology
Behavior, Animal
Biological Sciences
Brain
Brain-Derived Neurotrophic Factor - genetics
Brain-Derived Neurotrophic Factor - metabolism
Dentate Gyrus - metabolism
Dentate Gyrus - pathology
Depression - genetics
Depression - metabolism
Depression - pathology
Epigenesis, Genetic
Epigenetics
Gene expression
Glutamic Acid - genetics
Glutamic Acid - metabolism
Histones - genetics
Histones - metabolism
Male
Mice
Mice, Mutant Strains
Neurological disorders
p300-CBP Transcription Factors - genetics
p300-CBP Transcription Factors - metabolism
Receptors, Metabotropic Glutamate - genetics
Receptors, Metabotropic Glutamate - metabolism
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Stress
Stress, Psychological - genetics
Stress, Psychological - metabolism
Stress, Psychological - pathology
Synaptic Transmission
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1516016112