scholarly journals Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder

2020 ◽  
Author(s):  
Eleonora Gatta ◽  
Alessandro Guidotti ◽  
Vikram Saudagar ◽  
Dennis R Grayson ◽  
Dario Aspesi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Promoter Region ◽  
Alcohol Use Disorder ◽  
Hydroxysteroid Dehydrogenase ◽  
Fine Tuning ◽  
Translocator Protein ◽  
Gas Chromatography Mass Spectrometry ◽  
Gabaergic Neurotransmission

Abstract Background Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. Methods In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. Results The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. Conclusion Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

Alcohol Use Disorder

2018 ◽  
Author(s):  
Igor Ponomarev
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Critical Discussion ◽  
Epigenetic Mechanisms ◽  
Future Directions ◽  
Clinically Significant ◽  
Early Life Exposures ◽  
The Brain ◽  
Epigenetic Research

Alcohol use disorder (AUD) is characterized by clinically significant impairments in health and social function. Epigenetic mechanisms of gene regulation may provide an attractive explanation for how early life exposures to alcohol contribute to the development of AUD and exert lifelong effects on the brain. This chapter provides a critical discussion of the role of epigenetic mechanisms in AUD etiology and the potential of epigenetic research to improve diagnosis, evaluate risks for alcohol-induced pathologies, and promote development of novel therapies for the prevention and treatment of AUD. Challenges of the current epigenetic approaches and future directions are also discussed.

A Developmental Perspective on the Genetic Basis of Alcohol Use Disorder

2018 ◽  
Author(s):  
Elisa M. Trucco ◽  
Gabriel L. Schlomer ◽  
Brian M. Hicks
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Developmental Perspective ◽  
Relative Contribution ◽  
Intermediate Phenotypes ◽  
Problematic Alcohol ◽  
Age Related ◽  
Genetic And Environmental Factors ◽  
Problematic Alcohol Use

Approximately 48–66% of the variation in alcohol use disorders is heritable. This chapter provides an overview of the genetic influences that contribute to alcohol use disorder within a developmental perspective. Namely, risk for problematic alcohol use is framed as a function of age-related changes in the relative contribution of genetic and environmental factors and an end state of developmental processes. This chapter discusses the role of development in the association between genes and the environment on risk for alcohol use disorder. Designs used to identify genetic factors relevant to problematic alcohol use are discussed. Studies examining developmental pathways to alcohol use disorder with a focus on endophenotypes and intermediate phenotypes are reviewed. Finally, areas for further investigation are offered.

scholarly journals The role of pubertal timing in the link between family history of alcohol use disorder and late adolescent substance use

2020 ◽  
Vol 210 ◽  
pp. 107955
Author(s):  
Alexander S. Weigard ◽  
Jillian E. Hardee ◽  
Robert A. Zucker ◽  
Mary M. Heitzeg ◽  
Adriene M. Beltz
Keyword(s):  
Substance Use ◽  
Family History ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Pubertal Timing ◽  
Adolescent Substance Use ◽  
Late Adolescent ◽  
Adolescent Substance ◽  
History Of

Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow‐up study

2021 ◽  
Author(s):  
Soundarya Soundararajan ◽  
Arpana Agrawal ◽  
Meera Purushottam ◽  
Shravanthi Daphne Anand ◽  
Bhagyalakshmi Shankarappa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Follow Up Study ◽  
Over Time

Emotional difficulties among individuals with alcohol use disorder: the mediating role of psychological mechanisms linked to mindfulness

2020 ◽  
Vol 25 (5) ◽  
pp. 561-568
Author(s):  
Marco Cavicchioli ◽  
Pietro Ramella ◽  
Giulia Simone ◽  
Giulia Vassena ◽  
Mariagrazia Movalli ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Emotional Difficulties ◽  
Mediating Role ◽  
Psychological Mechanisms

scholarly journals Unraveling the functional role of DNA methylation using targeted DNA demethylation by steric blockage of DNA methyltransferase with CRISPR/dCas9

2020 ◽  
Author(s):  
Daniel M. Sapozhnikov ◽  
Moshe Szyf
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Region ◽  
Dna Methyltransferase ◽  
Dna Demethylation ◽  
New Method ◽  
Inducible Promoters ◽  
Specific Targeting ◽  
Main Effect

AbstractAlthough associations between DNA methylation and gene expression were established four decades ago, the causal role of DNA methylation in gene expression remains unresolved. Different strategies to address this question were developed; however, all are confounded and fail to disentangle cause and effect. We developed here a highly effective new method using only deltaCas9(dCas9):gRNA site-specific targeting to physically block DNA methylation at specific targets in the absence of a confounding flexibly-tethered enzymatic activity, enabling examination of the role of DNA methylation per se in living cells. We show that the extensive induction of gene expression achieved by TET/dCas9-based targeting vectors is confounded by DNA methylation-independent activities, inflating the role of DNA methylation in the promoter region. Using our new method, we show that in several inducible promoters, the main effect of DNA methylation is silencing basal promoter activity. Thus, the effect of demethylation of the promoter region in these genes is small, while induction of gene expression by different inducers is large and DNA methylation independent. In contrast, targeting demethylation to the pathologically silenced FMR1 gene targets robust induction of gene expression. We also found that standard CRISPR/Cas9 knockout generates a broad unmethylated region around the deletion, which might confound interpretation of CRISPR/Cas9 gene depletion studies. In summary, this new method could be used to reveal the true extent, nature, and diverse contribution to gene regulation of DNA methylation at different regions.

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