2010 Fiscal Year Final Research Report
Analysis of the epigenetic regulation in the mechanism of antidepressants.
| Project/Area Number |
21791134
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Psychiatric science
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| Research Institution | Yamaguchi University |
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Principal Investigator |
OTUKI Koji Yamaguchi University, 大学院・医学系研究科, 助教 (10535256)
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| Project Period (FY) |
2009 – 2010
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| Keywords | antidepressant / GDNF / HDAC |
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| Research Abstract |
We have previously developed an animal model of depression : BALB/c mice exhibited the increase in depression-like behaviors and the decreased expression level of glial cell line-derived neurotrophic factor (GDNF) mRNA in the striatum after a 6-wk of chronic ultra-mild stress episode. Importantly, the reduction of GDNF mRNA in the stressed BALB/c mice was reversed by chronic treatment with antidepressant imipramine. Therefore in this study, we aimed to clarify the molecular mechanism underlying the changes in the GDNF expression by antidepressants. First, we examined the effects of antidepressants, mood stabilizers, an anxiolytic drug and an antipsychotic drug on the expression of GDNF mRNA in C6 glial cells. The expression of GDNF mRNA was increased by all antidepressants used and valproate. Next, since the valproate has been known to act as a histone deacetylase inhibitor, we examined the effects of antidepressants histone acetylation. ChIP assay revealed that the levels of histone H3 and H4 acetylation at the GDNF promoter were enhanced by antidepressants. In addition, HDAC4 significantly decreased the transcriptional activity of GDNF promoter and inhibited the induction of GDNF expression by antidepressants. Thus, our data suggest that antidepressants increase transcriptional activity of GDNF gene through the modulation of histone acetylation.
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[Journal Article] Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.2011
Author(s)
Uchida S, Hara K, Kobayashi A, Fujimoto M, Otsuki K, Yamagata H, Hobara T, Abe N, Higuchi F, Shibata T, Hasegawa S, Kida S, Nakai A, Watanabe Y.
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Journal Title
Proc Natl Acad Sci U S A. 108
Pages: 1681-86
Peer Reviewed
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[Remarks] ホームページ等
