title: Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats.
abstract: Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea;
authors.forename: Miyeon
authors.initials: M
authors.lastname: Choi
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea;
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea;
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Wang
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea;
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Ko
authors.affiliation: Department of Psychology, Korea University, Seoul 136-701, Korea;
authors.forename: Mihee
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Psychology, Korea University, Seoul 136-701, Korea;
authors.forename: June-Seek
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea;
authors.forename: Yong-Seok
authors.identifier: http://orcid.org/0000-0001-5062-7408
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea; hyeonson@hanyang.ac.kr.
authors.forename: Hyeon
authors.initials: H
authors.lastname: Son
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D064326:MEF2 Transcription Factors / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D064326:MEF2 Transcription Factors; D007649:Ketamine; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases
keywords: HDAC; depression; hippocampus; ketamine