Department of Developmental Molecular Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Neuropsychopharmacology. 2011 Jul;36(8):1714-28. doi: 10.1038/npp.2011.52. Epub 2011 Apr 13.
The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/- mice treated with saline, but not in Mthfr+/- mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA Aα2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA Aα2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr deficiency in neurodevelopmental disorders.
亚甲基四氢叶酸还原酶（MTHFR）是同型半胱氨酸和叶酸代谢途径的一部分，影响 DNA、RNA 和蛋白质的甲基化。Mthfr 缺乏被报道为神经发育障碍的风险因素，如自闭症谱系障碍和精神分裂症。新生期 GABA 能系统的破坏也与行为结果有关。已经表明，Mthfr 缺乏的表观遗传影响与新生期暴露于 GABA 增强药物 vigabatrin（GVG）在小鼠中的相互作用具有性别依赖性，对小鼠焦虑具有性别独立性的记忆障碍作用。在这里，我们显示 Mthfr 缺乏与新生期 GABA 增强相互作用，改变雌性而非雄性小鼠的社会行为。这种损伤与雌性皮质中涉及兴奋性突触可塑性的蛋白质的性别依赖性增强有关。在接受新生期 GVG 处理的野生型小鼠和接受生理盐水处理的 Mthfr+/-小鼠中，Reelin 和脆性 X 智力低下蛋白 1（FMRP）水平以及膜 GluR1/GluR2 比值升高，但在接受 GVG 处理的 Mthfr+/-小鼠中则没有升高，与对照组相比（用生理盐水处理的野生型）。在雄性小鼠皮质中观察到这些蛋白质水平的轻微影响，这可能是由于基础蛋白水平较高所致。在 GABA 途径中也观察到性别、基因型和处理之间的相互作用。在雌性小鼠中，所有测试组的 GABA Aα2/gephyrin 比值均受到抑制；在雄性小鼠中，观察到 GABA Aα2/gephyrin 的基因型特异性增强。这些基因的转录没有受到影响，这表明这些基因的转录后调节。总之，这些发现表明 Mthfr 缺乏可能以性别依赖的方式与新生期 GABA 增强相互作用，从而中断突触功能。这可能说明了 Mthfr 缺乏在神经发育障碍中的表观遗传参与的一种可能机制。
