DNA Methylation in the Medial Prefrontal Cortex Regulates Alcohol-Induced Behavior and Plasticity
DNA Methylation in the Medial Prefrontal Cortex Regulates Alcohol-Induced Behavior and Plasticity
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DOI：
10.1523/jneurosci.4571-14.2015
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发表时间：
2015-04-15
影响因子：
5.3
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
--
作者：
Barbier, Estelle;Tapocik, Jenica D.;Heilig, Markus
最近的研究表明，酒精中毒与DNA甲基化之间存在关联，DNA甲基化是一种可以调节基因转录长期变化的机制。在这里，我们研究了DNA甲基化在酒精依赖史引起的长期行为和分子变化中的作用。为了寻找持续而非急性依赖诱导的神经适应的机制，我们研究了DNA甲基化在酒精依赖后戒断3周大鼠中调节内侧前额叶皮质(MPFC)基因表达和酒精相关行为的作用。依赖后的大鼠表现出酒精摄入量的增加，这与DNA甲基化增加以及编码参与mPFC神经递质释放的突触蛋白的基因表达减少有关。注射DNA甲基转移酶抑制剂RG108既可以防止酒精消费的增加，也可以防止依赖后依赖大鼠7个转录本中的4个转录下调。具体地说，RG108处理直接逆转了突触素2(Syt2)基因表达的下调和其第一外显子CpG#5的高甲基化。慢病毒抑制mPFC中Syt2的表达增加了对酒精的厌恶，支持了Syt2在强迫症行为中的机械作用。我们的发现确定了DNA甲基化在类似酒精依赖的行为表型中的功能作用，以及可能介导其影响的候选基因网络。总之，这些数据为DNA甲基转移酶作为酒精中毒的潜在治疗靶点提供了新的证据。
Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.