Methionine increases BDNF DNA methylation and improves memory in epilepsy.
Methionine increases BDNF DNA methylation and improves memory in epilepsy.
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DOI：
10.1002/acn3.183
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发表时间：
2015-04
影响因子：
5.3
通讯作者：
Lubin, Farah D.
中科院分区：
文献类型：
--
作者：
Parrish, R. Ryley;Buckingham, Susan C.;Mascia, Katherine L.;Johnson, Jarvis J.;Matyjasik, Michal M.;Lockhart, Roxanne M.;Lubin, Farah D.
颞叶癫痫（TLE）患者即使在癫痫发作得到有效控制的情况下也会表现出记忆障碍的迹象。令人惊讶的是，涉及TLE相关记忆障碍的潜在分子机制仍然难以捉摸。记忆巩固需要海马中基因的表观遗传转录调控;因此，我们的目的是确定表观遗传DNA甲基化机制如何影响癫痫海马中记忆允许基因的学习诱导转录。使用红藻氨酸啮齿动物模型的TLE和集中在脑源性神经营养因子（Bdnf）基因作为一个候选的DNA甲基化介导的转录，我们分析了DNA甲基化水平在癫痫大鼠学习。在检测到Bdnf基因的异常DNA甲基化后，我们在TLE啮齿动物模型中研究了DNA甲基化改变对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相关。亚硫酸氢盐测序显示，在记忆巩固过程中，癫痫海马中BdnfDNA甲基化水平的降低与BdnfmRNA的异常高水平密切相关。在记忆巩固过程中，通过甲硫氨酸（Met）补充甲基可增加癫痫海马中BdnfDNA甲基化并降低BdnfmRNA水平。在癫痫动物中，甲硫氨酸给药减少了发作间期峰电位活动，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Bdnf DNA甲基化、Bdnf基因表达和海马依赖性记忆的拯救作用通过DNA甲基转移酶阻断而减弱。我们的研究结果表明，在癫痫海马DNA甲基化的操作应被视为一个可行的治疗选择，以改善与TLE相关的记忆障碍。
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.
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影响因子：
6.1
作者：
Khan, Omar I.;Zhao, Qian;Miller, Forrest;Holmes, Gregory L.
通讯作者：
Holmes, Gregory L.
影响因子：
3.5
作者：
Buzsáki, G
通讯作者：
Buzsáki, G
影响因子：
2.7
作者：
Assini, Fabricio Luiz;Duzzioni, Marcelo;Takahashi, Reinaldo Naoto
通讯作者：
Takahashi, Reinaldo Naoto
影响因子：
4
作者：
Alonso, M;Vianna, MRM;Medina, JH
通讯作者：
Medina, JH
DOI：
10.1097/nen.0b013e31819ba737
发表时间：
2009-04-01
影响因子：
3.2
作者：
Kobow, Katja;Jeske, Ina;Bluemcke, Ingmar
通讯作者：
Bluemcke, Ingmar