Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity
Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity
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DOI：
10.1073/pnas.1516016112
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发表时间：
2015-12-01
影响因子：
11.1
通讯作者：
McEwen, Bruce S.
中科院分区：
文献类型：
--
作者：
Nasca, Carla;Zelli, Danielle;McEwen, Bruce S.
兴奋性氨基酸在应激源对大脑的适应性和有害作用中起着关键作用，谷氨酸稳态失调与精神和神经系统疾病有关。在这里，我们阐明了海马体在慢性应激史和熟悉的和新的急性应激源之间的相互作用中表观遗传可塑性的机制，这些相互作用改变了焦虑和抑郁样行为的表达。我们证明，急性约束和急性强迫游泳应激源对幼稚小鼠和有慢性约束应激（CRS）史的小鼠的这些行为产生不同的影响。它们揭示了表观遗传上下调节的关键作用，这些调节被认为是突触前2型代谢性谷氨酸（mGlu2）受体和突触后NR1/NMDA受体在海马，特别是在齿状回（DG），一个活跃的神经发生区域和抗抑郁治疗的目标。我们发现DG长期增强（LTP）的变化与行为反应相似，对相同的急性约束应激源的习惯化和对新的强迫游泳应激源的敏化。在CRS后的WT小鼠和具有BDNF功能缺失等位基因（BDNF Val66Met）的非应激小鼠中，我们发现当施加急性应激源时，组蛋白乙酰化的表观遗传激活因子P300通过组蛋白-3-lysine-27-乙酰化（H3K27Ac）在海马mGlu2的动态上下调节中起关键作用。这些海马反应揭示了表观遗传可塑性的窗口，可能有助于治疗谷氨酸能传递失调的疾病。
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.