Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2.
Ryan W LoganAngela R OzburnRachel N AreyKyle D KetchesinAlicia WinquistAndrew CrainBrian T D TobeDarius Becker-KrailMatthew B JarpeXiangning XueWei ZongZhiguang HuoPuja K ParekhXiyu ZhuEthan FitzgeraldHui ZhangJeffrey Oliver-SmithLauren M DePoyMariah A HildebrandEvan Y SnyderGeorge C TsengColleen A McClungPublished in: Molecular psychiatry (2020)
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.
Keyphrases
- histone deacetylase
- bipolar disorder
- induced pluripotent stem cells
- major depressive disorder
- end stage renal disease
- endothelial cells
- chronic kidney disease
- ejection fraction
- type diabetes
- cell proliferation
- high fat diet induced
- spinal cord
- single cell
- adipose tissue
- peritoneal dialysis
- metabolic syndrome
- cell therapy
- pluripotent stem cells