Comprehensive understanding of pathobiology of mental illnesses by examining relationship between polyunsaturated fatty acids and oligodendrocyte precursor cells

精神分裂症病因学的一个强有力的假说是“神经发育异常说”，该假说认为大脑发育期的细微损伤“是精神分裂症易感性的基础。我们通过在神经发育阶段用多不饱和脂肪酸（PUFA）缺乏的饮食饲养小鼠（PUFA（-）-小鼠）来验证这一理论。PUFA（-）-小鼠表现出精神分裂症早期的行为表型。有趣的是，在PUFA（-）小鼠的额叶皮层中，髓鞘相关基因的表达下调，就像精神分裂症患者死后的大脑一样。我们发现，上述下调是由转录因子基因TF-A和TF-B的表达减少引起的。PUFA（-）小鼠脑组织中TF-A和TF-B基因启动子区的甲基化水平升高，可能是导致TF-A和TF-B基因表达降低的原因。

One of the cogent hypotheses of schizophrenia etiology is"neurodevelopmental abnormality theory", which proposes that subtle insults during brain developmental period"underlies the susceptibility of schizophrenia. We tested this theory by raising mice with polyunsaturated fatty acid (PUFA)-deficient diet during neurodevelopmental stage (PUFA(-)-mice). The PUFA(-)-mice displayed behavioral phenotypes reminiscent of early stage of schizophrenia. Interestingly, myelin-related genes were down-regulated in the frontal cortex of PUFA(-)-mice as in the postmortem brains of schizophrenia. We revealed that the above downregulations are caused by decreased expressions of transcription factor genes, TF-A and TF-B. The promoter regions of TF-A and TF-B from the brains of PUFA(-)-mice showed elevated DNA methylation, which probably lead to the lowered expressions of TF-A and TF-B.