Department of Neurobiology, University of Alabama - Birmingham Birmingham, Alabama.
Department of Chemistry, Weber State University Ogden, Utah.
Ann Clin Transl Neurol. 2015 Apr;2(4):401-16. doi: 10.1002/acn3.183. Epub 2015 Mar 12.
Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus.
Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model.
We found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade.
Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.
颞叶癫痫（TLE）患者即使在癫痫发作得到药物控制后，也会出现记忆障碍的迹象。令人惊讶的是，与 TLE 相关的记忆障碍的潜在分子机制仍不清楚。记忆巩固需要在海马体中对基因进行表观转录调控；因此，我们旨在确定表观 DNA 甲基化机制如何影响癫痫海马体中学习诱导的记忆许可基因的转录。
使用海人酸啮齿动物 TLE 模型，并将脑源性神经营养因子（Bdnf）基因作为 DNA 甲基化介导转录的候选基因，我们分析了学习后癫痫大鼠中的 DNA 甲基化水平。在检测到 Bdnf 基因的异常 DNA 甲基化后，我们研究了改变的 DNA 甲基化对我们的 TLE 啮齿动物模型中海马依赖性记忆形成的功能影响。
我们发现，行为驱动的 BdnfDNA 甲基化与海马依赖性记忆缺陷有关。亚硫酸氢盐测序显示，在记忆巩固期间，癫痫海马体中 BdnfDNA 甲基化水平降低与 BdnfmRNA 水平异常升高强烈相关。通过蛋氨酸（Met）进行甲基补充增加了 BdnfDNA 甲基化并降低了癫痫海马体中的 BdnfmRNA 水平。Met 给药减少了癫痫动物的发作间尖峰活动，增加了θ节律功率，并逆转了记忆缺陷。Met 治疗对学习诱导的 BdnfDNA 甲基化、Bdnf 基因表达和海马依赖性记忆的挽救作用，被 DNA 甲基转移酶阻断所减弱。
我们的研究结果表明，在癫痫海马体中操纵 DNA 甲基化应被视为改善与 TLE 相关的记忆障碍的可行治疗选择。
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