Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.
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.
Tsankova
Nadia M
NM
The University of Texas Southwestern Medical Center, Department of Psychiatry and Center for Basic Neuroscience, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Berton
Olivier
O
Renthal
William
W
Kumar
Arvind
A
Neve
Rachel L
RL
Nestler
Eric J
EJ
D000107:Acetylation; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D013315:Stress, Psychological / Q000378:metabolism
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D002843:Chromatin; D006657:Histones; D007099:Imipramine