...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The international journal of neuropsychopharmacology >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)
【24h】

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)

机译：酒精使用障碍（AUD）的小脑中单碳代谢和DNA甲基化富集对δ含GABA A受体表达的新兴作用

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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. alcohol , cerebellum , GABAA receptor , one-carbon metabolism , methylation Significance Statement The cerebellum, an area of the brain exerting a strong control on posture, motor, and cognitive function, is particularly sensitive to the effects of both acute and chronic alcohol exposure. Alcohol-induced facilitation of GABAergic neurotransmission impairs cerebellar function by increasing GABA release from Golgi cells onto the extrasynaptic GABAA receptors. Our study demonstrates an enhancement of the 1-carbon metabolism leading to an increased DNA “methylation index” in cerebellum of alcohol use disorders (AUD) subjects. These changes were associated with a selective hypermethylation of the promoter region and a reduced expression of the extrasynaptic δ-containing GABAA receptor located on cerebellar granule cells. This work provides evidence for a central role of DNA methylation in the chronic alcohol-induced neuroadaptive changes of extrasynaptic (tonic) GABAA receptor structure and function in the human cerebellum.
机译：背景小脑是大脑的一个区域，对急性和慢性饮酒的影响特别敏感。酒精暴露会通过增加GABA从高尔基体细胞释放到位于谷氨酸能颗粒细胞上的突触外α 6 /δ的GABA A 受体上而降低小脑Purkinje细胞的输出。在这里，我们研究了长期饮酒是否会引起GABA A 受体亚基表达的变化，以及这些变化是否与通过DNA甲基化的表观遗传机制的改变有关。方法我们使用了一组来自对照和慢性酒精中毒的死后小脑，这里定义为酒精使用障碍受试者（n = 25 /组）。 S-腺苷甲硫氨酸/ S-腺苷-高半胱氨酸通过高效液相色谱法测定。通过逆转录酶定量聚合酶链反应评估各种基因的mRNA水平。使用甲基化的DNA免疫沉淀和羟基甲基化的DNA免疫沉淀测定法来评估启动子甲基化富集。结果决定1-碳代谢关键酶的S-腺苷甲硫氨酸/ S-腺苷-同型半胱氨酸比率的编码的mRNA增加，表明在酒精使用障碍受试者中较高的“甲基化指数”。我们发现，酒精滥用障碍者小脑中δ亚基GABA A 受体启动子的甲基化增加与mRNA和蛋白质水平降低有关。在含有α 1 -或α 6 的GABA A 受体亚基中未观察到变化。 DNA-甲基转移酶（1、3A和3B）的表达未改变，而参与DNA脱甲基途径的TET1的mRNA水平却降低了。因此，δ亚基GABA A 受体启动子的甲基化增强可能是由于酒精诱导的DNA脱甲基化减少所致。结论总之，这些结果支持以下假设：异常的DNA甲基化途径可能与酒精中毒的小脑病理生理有关。此外，这项研究为DNA甲基化机制在酒精诱导的人小脑GABA A 受体功能的神经适应性变化中的重要作用提供了新的证据。酒精，小脑，GABA A 受体，一碳代谢，甲基化意义声明小脑是大脑中对姿势，运动和认知功能有强烈控制力的区域，对这种作用特别敏感急性和慢性酒精暴露。酒精诱导的GABA能神经传递促进通过增加高尔基细胞释放到突触外GABA A 受体的GABA释放而损害小脑功能。我们的研究表明，酒精滥用障碍（AUD）小脑的1-碳代谢增强，导致DNA“甲基化指数”增加。这些变化与启动子区域的选择性超甲基化和位于小脑颗粒细胞上的突触外含δ的GABA A 受体表达降低有关。这项工作为DNA甲基化在酒精诱导的人小脑中突触外（强直性）GABA A 受体结构和功能的神经适应性改变中的重要作用提供了证据。

著录项

相似文献

  • 外文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号