Antidepressant actions of histone deacetylase inhibitors

Herbert E. Covington, Ian Maze, Quincey C. LaPlant, Vincent F. Vialou, Yoshinori N. Ohnishi, Olivier Berton, Dan M. Fass, William Renthal, Augustus J. Rush, Emma Y. Wu, Subroto Ghose, Vaishnav Krishnan, Scott J. Russo, Carol Tamminga, Stephen J. Haggarty, Eric J. Nestler

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)11451-11460
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number37
DOIs
StatePublished - Sep 16 2009

ASJC Scopus subject areas

  • Neuroscience(all)

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    Covington, H. E., Maze, I., LaPlant, Q. C., Vialou, V. F., Ohnishi, Y. N., Berton, O., Fass, D. M., Renthal, W., Rush, A. J., Wu, E. Y., Ghose, S., Krishnan, V., Russo, S. J., Tamminga, C., Haggarty, S. J., & Nestler, E. J. (2009). Antidepressant actions of histone deacetylase inhibitors. Journal of Neuroscience, 29(37), 11451-11460. https://doi.org/10.1523/JNEUROSCI.1758-09.2009