Epigenetic control of GABAA-R expression by ethanol Public Deposited

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  • March 20, 2019
Creator
  • Bohnsack, John
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof.
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  • In Copyright
Advisor
  • Kash, Thomas
  • Crews, Fulton
  • Hodge, Clyde W.
  • Morrow, A. Leslie
  • Song, Juan
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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