Nature Neuroscience 9, 519 - 525 (2006)
Published online: 26 February 2006; | doi:10.1038/nn1659
Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant actionNadia M Tsankova1, Olivier Berton1, William Renthal1, Arvind Kumar1, Rachel L Neve2
& Eric J Nestler11
The University of Texas Southwestern Medical Center, Department of Psychiatry and Center for Basic Neuroscience, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA. 2
Harvard Medical School and McLean Hospital 202 MRC, Department of Psychiatry, 115 Mill Street, Belmont, Massachusetts 02178, USA.
Correspondence should be addressed to Eric J Nestler eric.nestler@utsouthwestern.edu To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I–V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.
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