Folate deficiency in a fetus is well known to cause neurodevelopment defects and development disorders. A low level of folate is also thought to be a risk for depression in adults. We have previously shown that post-weaning low folate induces neuronal immaturity in the dentate gyrus in mice, which suggests that low folate causes neuropsychological disorders via inhibition of neuronal maturation. In this study, we examined the effects of low folate on expression and epigenetic modification of genes involved in neuronal differentiation and maturation in primary mouse neural stem/progenitor cells (NSPCs) in vitro. An increase in Nestin (NSPC marker)-positive cells was observed in cells differentiated in a low folate medium for 3 days. An increase in βIII-tubulin (Tuj1: immature neuron marker)-positive cells and a decrease in microtubule-associated protein 2 (MAP2: mature neuron marker)-positive cells were observed in cells differentiated in a low folate medium for 7 days. In these cells, mRNA levels for genes involved in neuronal differentiation and maturation were altered. Hypomethylation of DNA, but not of histone proteins, was also observed at some promoters of these neuronal genes. The level of S-adenosylmethionine (SAM), a methyl donor, was decreased in these cells. The abnormalities in neural maturation and changes in gene expression in culture under low folate conditions were partially normalized by addition of SAM (5 μM). Based on these results, decreased SAM may induce DNA hypomethylation at genes involved in neuronal differentiation and maturation under low folate conditions, and this hypomethylation may be associated with low folate-induced neuronal immaturity.

众所周知，胎儿的叶酸缺乏会导致神经发育缺陷和发育障碍。低水平的叶酸也被认为是成年人患抑郁症的风险。我们之前已经表明断奶后低叶酸诱导小鼠齿状回神经元不成熟，这表明低叶酸通过抑制神经元成熟引起神经心理障碍。在这项研究中，我们研究了低叶酸对体外原代小鼠神经干/祖细胞 (NSPC)中参与神经元分化和成熟的基因表达和表观遗传修饰的影响. 在低叶酸培养基中分化 3 天的细胞中观察到巢蛋白（NSPC 标记）阳性细胞的增加。在低叶酸培养基中分化 7 天的细胞中观察到 βIII-微管蛋白（Tuj1：未成熟神经元标记）阳性细胞的增加和微管相关蛋白 2（MAP2：成熟神经元标记）阳性细胞的减少。在这些细胞中，参与神经元分化和成熟的基因的 mRNA 水平发生了改变。在这些神经元基因的一些启动子处也观察到 DNA 的低甲基化，但未观察到组蛋白的低甲基化。S级-腺苷甲硫氨酸 (SAM)，一种甲基供体，在这些细胞中减少。通过添加 SAM (5 μM)，神经成熟异常和低叶酸条件下培养物中基因表达的变化部分正常化。基于这些结果，在低叶酸条件下，降低的 SAM 可能诱导参与神经元分化和成熟的基因的 DNA 低甲基化，并且这种低甲基化可能与低叶酸诱导的神经元不成熟有关。