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The Journal of Neuroscience, September 16, 2009, 29(37):11451-11460; doi:10.1523/JNEUROSCI.1758-09.2009
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Behavioral/Systems/Cognitive
Antidepressant Actions of Histone Deacetylase Inhibitors
Herbert E. Covington III,1 Ian Maze,1 Quincey C. LaPlant,1 Vincent F. Vialou,1 Yoshinori N. Ohnishi,1 Olivier Berton,2 Dan M. Fass,3 William Renthal,4 Augustus J. Rush III,4 Emma Y. Wu,4 Subroto Ghose,4 Vaishnav Krishnan,4 Scott J. Russo,1 Carol Tamminga,4 Stephen J. Haggarty,3,5 andEric J. Nestler1,4 1Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, 2Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, 3Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts 02142, 4Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and 5Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114
Correspondence should be addressed to Eric J. Nestler, Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029-6574. Email: eric.nestler{at}mssm.edu
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.
Received April 12, 2009; revised July 23, 2009; accepted July 27, 2009.
Correspondence should be addressed to Eric J. Nestler, Fishberg Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029-6574. Email: eric.nestler{at}mssm.edu
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