Antidepressant actions of histone deacetylase inhibitors.
Antidepressant actions of histone deacetylase inhibitors.
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DOI：
10.1523/jneurosci.1758-09.2009
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发表时间：
2009-09-16
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影响因子：
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通讯作者：
Nestler EJ
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作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
抑郁症的持续症状表明大脑中存在稳定的分子适应性变化，这可能反映在染色质重塑水平上。我们发现，小鼠慢性社交挫败应激会导致伏隔核（一个重要的边缘脑区）中乙酰化组蛋白H3水平先短暂下降，随后持续升高。这种H3乙酰化的持续增加与伏隔核中组蛋白去乙酰化酶2（HDAC2）水平降低有关。在对抑郁症患者死后的伏隔核研究中也观察到了类似的效应。H3乙酰化和HDAC2表达的这些变化介导了持久的正向神经元适应性，因为向伏隔核中注入HDAC抑制剂（可增加组蛋白乙酰化）在社交挫败范式和其他行为测试中具有显著的抗抑郁样作用。HDAC抑制剂（MS - 275）的注入还逆转了慢性挫败应激对伏隔核中基因表达全局模式的影响，这通过微阵列分析确定，与标准抗抑郁药氟西汀的作用有惊人的相似之处。其表达被MS - 275选择性地正常化的应激调节基因可能为未来新型抗抑郁治疗的发展提供有希望的靶点。总之，这些发现为抑郁症和抗抑郁作用的潜在分子机制提供了新的见解，并支持了HDAC抑制剂以及可能其他作用于染色质结构水平的药物的抗抑郁潜力。
Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor (MS-275) infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant, fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.