Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat
Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat
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DOI：
10.1073/pnas.1204599109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Meaney, Michael J.
中科院分区：
文献类型：
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作者：
Bagot, Rosemary C.;Zhang, Tie-Yuan;Meaney, Michael J.
大鼠母体护理的变化会影响其海马形态和功能，以及后代海马依赖性学习和记忆测试的表现。对此类母体效应的分子基础的基因转录和 DNA 甲基化的初步全基因组分析表明，作为母体护理的功能，大鼠中 Grm1 基因的表观遗传状态和转录活性存在差异。 Grm1 编码 I 型代谢型谷氨酸受体 (mGluR1)，我们发现母亲的成年后代的海马体中 mGluR1 mRNA 和蛋白质增加，显示幼犬舔/梳理毛发的频率增加（即高 LG 母亲），这与 Grm1 甲基化的减少有关。 ChIP 检测显示，与低 LG 母亲相比，高 LG 成年后代海马中 Grm1 的组蛋白 3 赖氨酸 9 乙酰化和组蛋白 3 赖氨酸 4 三甲基化水平升高。这些组蛋白翻译后修饰高度相关，与 DNA 甲基化呈负相关，与转录呈正相关。 mGluR1 功能研究表明，与低 LG 母亲相比，高 LG 成年后代的海马 mGluR1 诱导的长期抑郁程度增加，配对脉冲抑郁 (PPD) 也增加。 PPD 是一种抑制反馈机制，可防止高频刺激期间谷氨酸过度释放。通过使用 mGluR1 选择性拮抗剂治疗，可以消除母体对长期抑郁症和 PPD 的影响。这些发现表明，产妇护理的变化可以通过谷氨酸能突触信号传导相关基因的表观遗传调控来影响海马功能和认知表现。
Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the Grm1 gene in the rat as a function of maternal care. Grm1 encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.e., high-LG mothers) that was associated with a decrease in the methylation of Grm1. ChIP assays showed increased levels of histone 3 lysine 9 acetylation and histone 3 lysine 4 trimethylation of Grm1 in hippocampus from the adult offspring of high-LG compared with low-LG mothers. These histone posttranslational modifications were highly correlated, and both associate inversely with DNA methylation and positively with transcription. Studies of mGluR1 function showed increased hippocampal mGluR1-induced long-term depression in the adult offspring of high-LG compared with low-LG mothers, as well as increased paired-pulse depression (PPD). PPD is an inhibitory feedback mechanism that prevents excessive glutamate release during high-frequency stimulation. The maternal effects on both long-term depression and PPD were eliminated by treatment with an mGluR1-selective antagonist. These findings suggest that variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes implicated in glutamatergic synaptic signaling.