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Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Summary: Sustained hippocampal chromatin regulation in a
mouse model of depression and antidepressant action
Nadia M Tsankova1, Olivier Berton1, William Renthal1, Arvind Kumar1, Rachel L Neve2 & Eric J Nestler1
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 (IV) 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.
Chronic stress can precipitate depression in susceptible individuals but
the underlying molecular pathogenesis in the brain remains elusive.
Similarly, antidepressants provide important relief in many individuals
but their mechanisms of action are not completely understood1,2. The
hippocampus is one brain region that has been implicated in the
pathophysiology of depression: human patients suffering from depres-
sion have reduced hippocampal volumes3 and rodents show stress-


Source: Alford, Simon - Department of Biological Sciences, University of Illinois at Chicago


Collections: Biology and Medicine