DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats
DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats
复制标题
记忆基因的 DNA 甲基化操作与七氟烷诱导的老年大鼠认知障碍有关
DOI：
10.3389/fnagi.2020.00211
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发表时间：
2020-08-18
影响因子：
4.8
通讯作者：
Zheng, Hui
中科院分区：
文献类型：
--
作者：
Ni, Cheng;Qian, Min;Zheng, Hui
DNA甲基化是参与基因转录调控的重要表观遗传机制。在神经元活动和记忆基因中观察到与年龄相关的启动子甲基化增加，并参与神经系统疾病。然而，DNA甲基化在麻醉相关认知障碍中记忆基因调控的位置和确切机制仍有待确定。本实验研究了七氟醚麻醉对老龄大鼠海马记忆基因转录的影响。然后，我们研究了相关基因的DNA甲基化变化，并验证了DNA甲基化失调是否会导致麻醉诱导的认知障碍。结果表明，七氟醚麻醉可下调Arc、Bdnf、Reln三个记忆基因的mRNA和蛋白水平，并伴有启动子超甲基化，增加Dnmt1、Dnmt3a、Mecp2的表达，最终导致海马依赖性记忆受损。此外，5-Aza拯救的七氟醚抑制DNA超甲基化导致记忆基因表达减少和认知障碍。这些发现为全麻致老年脑认知功能障碍的病理生理提供了表观遗传学的认识。
DNA methylation is an essential epigenetic mechanism involving in gene transcription modulation. An age-related increase in promoter methylation has been observed for neuronal activity and memory genes, and participates in neurological disorders. However, the position and precise mechanism of DNA methylation for memory gene modulation in anesthesia related cognitive impairment remained to be determined. Here, we studied the effects of sevoflurane anesthesia on the transcription of memory genes in the aged rat hippocampus. Then, we investigated changes in DNA methylation of involved genes and verified whether dysregulated DNA methylation would contribute to anesthesia induced cognitive impairment. The results indicated that sevoflurane anesthesia down-regulated the mRNA and protein levels of three memory genes, Arc, Bdnf, and Reln, which were accompanied with promoter hypermethylation and increased Dnmt1, Dnmt3a, and Mecp2 expression, and finally impaired hippocampus dependent memory. Furthermore, inhibition of DNA hypermethylation by 5-Aza rescued sevoflurane induced memory gene expression decrease and cognitive impairment. These findings provide an epigenetic understanding for the pathophysiology of cognitive impairment induced by general anesthesia in aged brain.