Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2

Ryan W. Logan, Angela R. Ozburn, Rachel N. Arey, Kyle D. Ketchesin, Alicia Winquist, Andrew Crain, Brian T.D. Tobe, Darius Becker-Krail, Matthew B. Jarpe, Xiangning Xue, Wei Zong, Zhiguang Huo, Puja K. Parekh, Xiyu Zhu, Ethan Fitzgerald, Hui Zhang, Jeffrey Oliver-Smith, Lauren M. DePoy, Mariah A. Hildebrand, Evan Y. SnyderGeorge C. Tseng, Colleen A. McClung

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.

Original languageEnglish (US)
Pages (from-to)4066-4084
Number of pages19
JournalMolecular Psychiatry
Issue number8
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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