Antidepressant Actions of Histone Deacetylase Inhibitors

作者：Herbert E. Covington, Ian S. Maze, Quincey C. LaPlant, Vincent F. Vialou, Yoshinori N. Ohnishi, Olivier Berton, Daniel M. Fass, William R. Renthal, Augustus John Rush, Emma Y. Wu, Subroto Ghose, Vaishnav Krishnan, Scott J. Russo, Carol A. Tamminga, Stephen J. Haggarty, Eric J. Nestler · 发表于：Journal of Neuroscience · 年份：2009 · DOI：10.1523/jneurosci.1758-09.2009 · 被引用次数：633 · 研究领域：Histone Deacetylase Inhibitors Research、Nuclear Receptors and Signaling、Genetics and Neurodevelopmental Disorders

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...