Abstract
Recent reports have suggested that epigenetic gene regulations are closely associated with the development of stress vulnerability, and also contribute to behavioral responses to chronic stress and antidepressants. There are evidences suggesting that histone deacetylase (HDAC) inhibitors have modest antidepressant-like effects in rodents. However, molecular mechanisms of antidepressant actions induced by HDAC inhibitors remain unclear. The purpose of this study is to clarify molecular mechanisms of antidepressant actions by HDAC inhibitors. First, we confirmed the rapid antidepressant effect of a HDAC inhibitor, SAHA using the model mouse for depression. We found that subchronic treatment with SAHA reversed the increased depression-related behaviors in mice subjected to chronic ultra mild stress. In addition, subchronic treatment with SAHA enhanced the expression of calcium/calmodulin-dependent protein kinase (CaMK) IIß mRNA in the hippocampus of stressed mice. However, subchronic treatment with imipramine did not affect the expression of CaMKIIß, as well as depression-related behaviors in stressed mice. These data suggest that SAHA has a rapid antidepressant action, and that the induction of CaMKIIß in the hippocampus by SAHA may contribute to the antidepressant action. Furthermore, we found the modest induction of CaMKIIß mRNA by HDAC inhibitors in the neuroblastoma Neuro 2a cells. Also, the number of differentiated cells was significantly increased by HDAC inhibitors. Importantly, the induction of cell differentiation by HDAC inhibitors was blocked by treatment with CaMKII inhibitors and CaMKIIß knockdown. Thus, our data suggest that the induction of CaMKIIß by HDAC inhibitors in the hippocampus might be involved in the structural plasticity and the subsequent antidepressant action.
