| Title | Antidepressant actions of histone deacetylase inhibitors. | | Author(s) | Covington HE, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AJ, Wu EY, Ghose S, Krishnan V, Russo SJ, Tamminga C, Haggarty SJ, Nestler EJ | | Institution | Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA. | | Source | J Neurosci 2009 Sep 16; 29(37):11451-60. | | MeSH | Analysis of Variance
Animals
Antidepressive Agents
Behavior, Animal
Benzamides
Depression
Disease Models, Animal
Dominance-Subordination
Dose-Response Relationship, Drug
Enzyme Inhibitors
Fluoxetine
Food Preferences
Gene Expression Profiling
Gene Expression Regulation, Enzymologic
Histone Deacetylases
Histones
Humans
Hydroxamic Acids
Interpersonal Relations
Male
Mice
Mice, Inbred C57BL
Models, Biological
Nucleus Accumbens
Oligonucleotide Array Sequence Analysis
Postmortem Changes
Pyridines
RNA, Messenger
Repressor Proteins
Sucrose
Sweetening Agents
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19759294 |
|
