Kalani Anuradha, Chaturvedi Pankaj, Kalani Komal, Kamat Pradip K, Chaturvedi Poonam
Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA.
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India; Pharmacology Department and Toxicology, Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA.
Neural Regen Res. 2019 Jul;14(7):1247-1254. doi: 10.4103/1673-5374.251333.
Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B (0.01 mg/kg), and B (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4 week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B/B can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018.
记忆表观遗传学是指由于表观遗传修饰导致的记忆丧失，这可能是由于参与认知功能的基因沉默所致，而这正是当前研究的基础。我们推测，一种高蛋氨酸和低维生素的饮食会通过增加整体DNA甲基化，进而使编码参与神经发生、轴突导向和突触可塑性维持的糖蛋白的netrin-1基因沉默，从而导致记忆障碍。将野生型（C57BL/6J）小鼠喂食含有过量蛋氨酸（1.2%）、低叶酸（0.08毫克/千克）、维生素B（0.01毫克/千克）和B（10.4毫克/千克）的饮食6周。每周使用被动回避试验检查小鼠的长期记忆功能，该试验从饮食的第四周开始确定恐惧驱动的长期记忆丧失。同样，从饮食的第4周开始，在小鼠中观察到脑5-甲基胞嘧啶百分比增加。通过甲基化敏感限制性内切酶-聚合酶链反应分析确定，喂食高蛋氨酸、低叶酸和维生素饮食的小鼠netrin-1蛋白表达降低，netrin-1基因启动子甲基化增加。通过高分辨率熔解和测序分析验证了netrin-1基因甲基化的增加。此外，通过给予能显著恢复长期恐惧驱动记忆的netrin，建立了netrin-1与记忆的关联。综上所述，这些结果表明，富含蛋氨酸且缺乏叶酸和维生素B/B的饮食会诱发学习和记忆缺陷。此外，数据表明其基因的高甲基化导致的netrin-1表达降低可能与记忆丧失有关。动物实验程序于2018年2月2日获得美国路易斯维尔大学机构动物护理和使用委员会批准（编号A3586-01）。
