Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 112; no. 51; pp. 15755 - 15760
Main Authors Choi, Miyeon, Lee, Seung Hoon, Wang, Sung Eun, Ko, Seung Yeon, Song, Mihee, Choi, June-Seek, Kim, Yong-Seok, Duman, Ronald S., Son, Hyeon
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.12.2015
National Acad Sciences
Subjects
Active Transport, Cell Nucleus - drug effects
Analgesics
Animals
Antidepressants
Antidepressive Agents - pharmacology
Biological Sciences
Cell Nucleus - metabolism
Cells, Cultured
Enzymes
Hippocampus - metabolism
Histone Deacetylases - metabolism
Ketamine - pharmacology
Kinases
MEF2 Transcription Factors - physiology
Phosphorylation
Rats
Rats, Sprague-Dawley
Rodents
depression
hippocampus
ketamine
HDAC
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Summary: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.
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Author contributions: H.S. designed research; M.C., S.H.L., S.E.W., S.Y.K., M.S., J.-S.C., and Y.-S.K. performed research; M.C. and H.S. analyzed data; and R.S.D. and H.S. wrote the paper.
Edited by Huda Akil, University of Michigan, Ann Arbor, MI, and approved November 12, 2015 (received for review July 15, 2015)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1513913112