Dataset Information

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

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.

SUBMITTER: Logan RW

PROVIDER: S-EPMC8141541 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Logan Ryan W RW Ozburn Angela R AR Arey Rachel N RN Ketchesin Kyle D KD Winquist Alicia A Crain Andrew A Tobe Brian T D BTD Becker-Krail Darius D Jarpe Matthew B MB Xue Xiangning X Zong Wei W Huo Zhiguang Z Parekh Puja K PK Zhu Xiyu X Fitzgerald Ethan E Zhang Hui H Oliver-Smith Jeffrey J DePoy Lauren M LM Hildebrand Mariah A MA Snyder Evan Y EY Tseng George C GC McClung Colleen A CA

Molecular psychiatry 20201124 8

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 ...[more]

PMID: 33235333

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Project description:Major depressive disorder (MDD) and bipolar disorder (BD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two diseases in clinical symptoms, treatment strategies, and genetic etiology. Here we use a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls) of Han Chinese origin to investigate their shared genetic basis, followed by exploration of the underlying mechanisms. The lead SNP in the Han Chinese meta-analysis, rs126277 at the 1q32.2 locus, also exhibited nominal associations with mood disorders as well as several sub-clinical phenotypes (e.g., mania) related to mood disorders (UK biobank samples) in European populations. Bulk tissue and single-cell eQTL studies suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brain tissues and cells, indicating possible involvement of this gene in mood disorders. We generated mice lacking Syt14 (Syt14–/–) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD). We found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in the mice. RNA-sequencing analyses of the hippocampus of Syt14–/– mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14–/– mice compared with control mice. And Syt14–/– mice exhibit aberrant glutamate signaling patterns in the hippocampus. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors and essential roles in synaptic function. While the current study provides clues for the pathological mechanisms of mood disorders, further investigations elucidating the detailed mechanisms by which SYT14 regulates mood disorders-related traits are needed.

Project description:Molecular recognition by enzymes is a complicated process involving thermodynamic energies governing protein-ligand interactions. In order to aid the estimation of inhibitory activity of compounds targeting an enzyme, several computational methods can be employed to dissect this intermolecular contact. Herein, we report a structural dynamics investigation of an epigenetic enzyme HDAC2 in differentiating its binding to various inhibitors within the sub-sites of its active site. Molecular dynamics (MD) simulation was employed to elucidate the intermolecular interactions as well as the dynamics behavior of ligand binding. MD trajectories of five distinct HDAC2-inhibitor complexes reveal that compounds lacking adequate contacts with the opening rim of the active site possess high fluctuation along the cap portion, thus weakening the overall affinity. Key intermolecular interactions determining the effective binding of inhibitors include hydrogen bonds with Gly154, Asp181, and Tyr308; hydrophobic interactions between Phe155/Phe210 and the linker region; and a pi-stacking with Arg39 at the foot pocket. Decomposition of the binding free energy calculated per-residue by MM/PBSA also indicates that the interactions within the internal foot pocket, especially with residues Met35, Leu144, Gly305, and Gly306, can contribute significantly to the ligand binding. Additionally, configurational entropy of the binding was estimated and compared to the scale of the binding free energy in order to assess its contribution to the binding and to differentiate various ligand partners. It was found that the levels of entropic contribution are comparable among a set of structurally similar carbamide ligands, while it is greatly different for the set of unrelated ligands, ranging from 2.75 to 16.38 kcal/mol for the five inhibitors examined. These findings exemplify the importance of assessing molecular dynamics as well as estimating the entropic contribution in evaluating the ligand binding mechanism.

Dataset Information

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

Publications

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

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