Covington Herbert E, Maze Ian, LaPlant Quincey C, Vialou Vincent F, Ohnishi Yoshinori N, Berton Olivier, Fass Dan M, Renthal William, Rush Augustus J, Wu Emma Y, Ghose Subroto, Krishnan Vaishnav, Russo Scott J, Tamminga Carol, Haggarty Stephen J, Nestler Eric J
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Neurosci. 2009 Sep 16;29(37):11451-60. doi: 10.1523/JNEUROSCI.1758-09.2009.
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 [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (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.
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，这可能在染色质重塑水平上得到体现。我们发现，小鼠的慢性社会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，随后持续上升。H3乙酰化的这种持续增加与伏隔核中组蛋白去乙酰化酶2（HDAC2）水平的降低有关。在死后研究的抑郁症患者的伏隔核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阳性神经元适应性变化，因为向伏隔核中注入HDAC抑制剂可增加组蛋白乙酰化，在社会挫败范式和其他行为试验中发挥强大的抗抑郁样作用。HDAC抑制剂[N-(2-氨基苯基)-4-[N-(吡啶-3-基甲氧基羰基)氨基甲基]苯甲酰胺（MS-275）]的注入还可逆转慢性挫败应激对伏隔核中基因表达全局模式的影响，这是通过微阵列分析确定的，与标准抗抑郁药氟西汀的作用具有显著相似性。其表达被MS-275选择性归一化的应激调节基因可能为新型抗抑郁治疗的未来发展提供有前景的靶点。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。
