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Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2
- Source :
- Molecular psychiatry
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Induced Pluripotent Stem Cells
Histone Deacetylase 2
Pharmacology
Article
Treatment of bipolar disorder
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
RNA interference
mental disorders
Medicine
Animals
Humans
Induced pluripotent stem cell
Molecular Biology
business.industry
Histone deacetylase 2
Valproic Acid
HDAC1
Ventral tegmental area
Histone Deacetylase Inhibitors
Psychiatry and Mental health
Mania
030104 developmental biology
medicine.anatomical_structure
lipids (amino acids, peptides, and proteins)
Histone deacetylase
medicine.symptom
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 14765578 and 13594184
- Volume :
- 26
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry
- Accession number :
- edsair.doi.dedup.....de3c998801c8fc52a7971dd952089690