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Biochem Biophys Res Commun. 2017 Aug 5;489(4):420-425. doi: 10.1016/j.bbrc.2017.05.157. Epub 2017 May 31.

Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

Author information

1
Graduate School of Biomedical Science and Engineering, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
2
Graduate School of Biomedical Science and Engineering, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea; Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea. Electronic address: yongsk@hanyang.ac.kr.
3
Graduate School of Biomedical Science and Engineering, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea; Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea. Electronic address: hyeonson@hanyang.ac.kr.

Abstract

Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine.

KEYWORDS:

BDNF; HDAC5; Hippocampus; Ketamine

PMID:
28577999
DOI:
10.1016/j.bbrc.2017.05.157
[Indexed for MEDLINE]

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