Fans of Aesop's fables know that slow and steady wins the race. However, the slow onset of therapeutic benefits can be agonizing for patients waiting several weeks for antidepressants to take effect. In the April issue of Nature Neuroscience, Tsankova et al. propose a mechanism for antidepressant action that accounts for this time lag, showing that depression and antidepressants both regulate transcription through modifications of chromatin structure.
The authors used social defeat stress as an animal model of clinical depression. Test mice were placed in the home cages of aggressive mice every day for 10 consecutive days. Four weeks later, the authors observed the test mice in cages with an aggressive mouse visible behind a plexiglass separator. Socially defeated mice spent less time near the aggressor than control mice. Chronic (4 week), but not acute (1 d), treatment with the antidepressant imipramine increased the time that defeated mice spent near the aggressor. Fluoxetine, a different type of antidepressant, had the same effect. The time course of relief validated the use of this model to study the delay in antidepressant action.
Brain-derived neurotrophic factor (BDNF) in the hippocampus is altered in animal models of stress and depression. In this study, total Bdnf mRNA decreased in the hippocampus 4 weeks following chronic social defeat. Chronic imipramine treatment reversed this effect. The mouse Bdnf gene has five non-coding exons that are alternatively spliced to form five unique promoters for the sixth common, coding exon. Bdnf transcripts with either the third or fourth exon promoter showed similar stress and antidepressant regulation to total Bdnf. Social defeat stress failed to regulate the remaining Bdnf transcripts.
The authors then used chromatin immunoprecipitation to examine the chromatin organization of the Bdnf transcripts that were regulated similarly to total Bdnf. Dimethylation at Lys27 on histone 3 correlates with more 'tightly wound'DNAand suppression of transcription. Dimethylation at this site increased 4 weeks following chronic social defeat stress on Bdnf promoters three and four. Hyperacetylation of the histone unwinds the DNA and encourages transcription. Chronic imipramine treatment increased histone 3 acetylation on Bdnf promoters three and four in socially defeated mice. Therefore, chronic social defeat stress compacted,and antidepressant treatment relaxed,Bdnf DNA in socially defeated mice.
Chronic imipramine treatment decreased expression of histone deacetylase 5 (HDAC5) mRNA in socially defeated mice. Overexpression of HDAC5 specifically in the hippocampus blocked the ability of imipramine to reverse social defeat stress. The transgene also reduced imipramine's effect on Bdnf transcripts three and four.
These data suggest that HDAC5 is an important target of antidepressant action. Sodium butyrate, a non-specific HDAC inhibitor, did not significantly alter the expression of social defeat. However, specific inhibitors of HDAC5 and other epigenetic regulators may prove promising as candidates for the next generation of antidepressants.