Abstract
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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Acknowledgements
We thank D. Theobald and T. Sasaki for helping with some of the mouse injections; K. Dennis (Vanderbilt University) for supplying the sodium bisulfite protocol for DNA methylation; and G. Petrov for graphic design expertise. This work was supported by grants from the US National Institute of Mental Health.
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Supplementary information
Supplementary Fig. 1
Structure of the Bdnf gene. (PDF 953 kb)
Supplementary Fig. 2
Changes in the H3-K27 di-methylation are specific for the Bdnf P3 and P4 promoters. (PDF 322 kb)
Supplementary Fig. 3
Changes in the H3 hyperacetylation and H3-K4 di-methylation are specific for the Bdnf P3 and P4 promoters. (PDF 451 kb)
Supplementary Fig. 4
H4 acetylation levels at the Bdnf P3 promoter are not changed after chronic defeat stress and imipramine treaments. (PDF 192 kb)
Supplementary Table 1
Locomotor activity in social defeat and control mice. (PDF 59 kb)
Supplementary Table 2
List of all primer sequences used. (PDF 57 kb)
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Tsankova, N., Berton, O., Renthal, W. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9, 519–525 (2006). https://doi.org/10.1038/nn1659
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DOI: https://doi.org/10.1038/nn1659
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