Emerging Role of One-Carbon Metabolism and DNA Methylation Enrichment on δ-Containing GABAA Receptor Expression in the Cerebellum of Subjects with Alcohol Use Disorders (AUD)
| العنوان: | Emerging Role of One-Carbon Metabolism and DNA Methylation Enrichment on δ-Containing GABAA Receptor Expression in the Cerebellum of Subjects with Alcohol Use Disorders (AUD) |
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| المؤلفون: | Alessandro Guidotti, Eleonora Gatta, Dennis R. Grayson, Dulal K. Bhaumik, David P. Gavin, James Auta, Subhash C. Pandey |
| المصدر: | International Journal of Neuropsychopharmacology |
| بيانات النشر: | Oxford University Press, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, medicine.medical_specialty, S-Adenosylmethionine, Adenosine, cerebellum, Gene Expression, Cerebellar Purkinje cell, Biology, Regular Research Articles, gamma-Aminobutyric acid, Mixed Function Oxygenases, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Proto-Oncogene Proteins, medicine, Humans, Immunoprecipitation, Pharmacology (medical), Methylated DNA immunoprecipitation, Epigenetics, RNA, Messenger, Promoter Regions, Genetic, Chromatography, High Pressure Liquid, Pharmacology, GABAA receptor, alcohol, Methylation, DNA Methylation, Middle Aged, one-carbon metabolism, Receptors, GABA-A, S-Adenosylhomocysteine, Carbon, Psychiatry and Mental health, Alcoholism, 030104 developmental biology, DNA demethylation, Endocrinology, Postmortem Changes, DNA methylation, Female, methylation, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction |
| الوصف: | Background Cerebellum is an area of the brain particularly sensitive to the effects of acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α6/δ-containing GABAA receptors located on glutamatergic granule cells. Here, we studied whether chronic alcohol consumption induces changes in GABAA receptor subunit expression and whether these changes are associated with alterations in epigenetic mechanisms via DNA methylation. Methods We used a cohort of postmortem cerebellum from control and chronic alcoholics, here defined as alcohol use disorders subjects (n=25/group). S-adenosyl-methionine/S-adenosyl-homocysteine were measured by high-performance liquid chromatography. mRNA levels of various genes were assessed by reverse transcriptase-quantitative polymerase chain reaction. Promoter methylation enrichment was assessed using methylated DNA immunoprecipitation and hydroxy-methylated DNA immunoprecipitation assays. Results mRNAs encoding key enzymes of 1-carbon metabolism that determine the S-adenosyl-methionine/S-adenosyl-homocysteine ratio were increased, indicating higher “methylation index” in alcohol use disorder subjects. We found that increased methylation of the promoter of the δ subunit GABAA receptor was associated with reduced mRNA and protein levels in the cerebellum of alcohol use disorder subjects. No changes were observed in α1- or α6-containing GABAA receptor subunits. The expression of DNA-methyltransferases (1, 3A, and 3B) was unaltered, whereas the mRNA level of TET1, which participates in the DNA demethylation pathway, was decreased. Hence, increased methylation of the δ subunit GABAA receptor promoter may result from alcohol-induced reduction of DNA demethylation. Conclusion Together, these results support the hypothesis that aberrant DNA methylation pathways may be involved in cerebellar pathophysiology of alcoholism. Furthermore, this work provides novel evidence for a central role of DNA methylation mechanisms in the alcohol-induced neuroadaptive changes of human cerebellar GABAA receptor function. |
| اللغة: | English |
| تدمد: | 1469-5111 1461-1457 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c9de0cc46673df8b2150e9b44108c3b http://europepmc.org/articles/PMC5716183 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3c9de0cc46673df8b2150e9b44108c3b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14695111 14611457 |
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