Du Yang, Li Xue-Song, Chen Lei, Chen Guang-Yang, Cheng Yong
Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Haidian District, Beijing, China.
Institute of Neuropsychiatric Diseases, The Third People's Hospital of Foshan, Guangdong, China.
Schizophr Bull. 2020 Apr 10;46(3):612-622. doi: 10.1093/schbul/sbz114.
Prenatal administration of mitotoxin methylazoxymethanol acetate (MAM) in rats produces behavioral, pharmacological, and anatomical abnormalities once offspring reach adulthood, thus establishing a widely used neurodevelopmental model of schizophrenia. However, the molecular aspects underlying this disease model are not well understood. Therefore, this study examines epigenetic and transcriptional dysregulation in the prefrontal cortex and hippocampus of MAM rats as these are brain regions closely associated with schizophrenia pathogenesis. Upon sequencing messenger and microRNA (mRNA and miRNA, respectively), differential expression was revealed in the prefrontal cortex and hippocampus between MAM- and saline-treated rats; sequencing data were validated by qualitative real-time polymerase chain reaction. Bioinformatic analyses demonstrated that the differentially expressed (DE) genes were strongly enriched in interactive pathways related to schizophrenia, including chemical synaptic transmission, cognition, and inflammatory responses; also, the potential target genes of the DE miRNAs were enriched in pathways related to synapses and inflammation. The blood of schizophrenia patients and healthy controls was further analyzed for several top DE mRNAs: DOPA decarboxylase, ret proto-oncogene, Fc receptor-like 2, interferon lambda receptor 1, and myxovirus (influenza virus) resistance 2. The results demonstrated that the expression of these genes was dysregulated in patients with schizophrenia; combining these mRNAs sufficiently differentiated schizophrenia patients from controls. Taken together, this study suggests that the MAM model has the potential to reproduce hippocampus and prefrontal cortex abnormalities, relevant to schizophrenia, at the epigenetic and transcriptional levels. These data also provide novel targets for schizophrenia diagnoses and treatments.
在大鼠孕期给予乙酸甲基偶氮甲醇（MAM，一种线粒体毒素），子代成年后会出现行为、药理和解剖学异常，从而建立了一种广泛应用的精神分裂症神经发育模型。然而，该疾病模型背后的分子机制尚不清楚。因此，本研究检测了MAM大鼠前额叶皮质和海马体中的表观遗传和转录失调情况，因为这些脑区与精神分裂症的发病机制密切相关。在分别对信使核糖核酸和微小核糖核酸（分别为mRNA和miRNA）进行测序时，发现MAM处理组和生理盐水处理组大鼠的前额叶皮质和海马体存在差异表达；测序数据通过定性实时聚合酶链反应进行了验证。生物信息学分析表明，差异表达（DE）基因在与精神分裂症相关的相互作用途径中高度富集，包括化学突触传递、认知和炎症反应；此外，DE miRNA的潜在靶基因在与突触和炎症相关的途径中富集。对精神分裂症患者和健康对照者的血液进一步分析了几个排名靠前的DE mRNA：多巴脱羧酶、原癌基因ret、Fc受体样2、干扰素λ受体1和黏液病毒（流感病毒）抗性2。结果表明，这些基因在精神分裂症患者中表达失调；将这些mRNA结合起来能够充分区分精神分裂症患者和对照者。综上所述，本研究表明MAM模型有可能在表观遗传和转录水平上重现与精神分裂症相关的海马体和前额叶皮质异常。这些数据也为精神分裂症的诊断和治疗提供了新的靶点。
