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.

中文翻译：

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对精神分裂症神经发育大鼠模型的表观遗传和转录调控进行网络分析，对转化研究具有重要意义。

一旦成年后成年大鼠在大鼠中进行线粒体毒素甲基乙酸甲酯氧化处理（MAM）会产生行为，药理和解剖学异常，从而建立了广泛使用的精神分裂症神经发育模型。但是，尚不清楚该疾病模型的分子基础。因此，本研究检查了MAM大鼠的前额叶皮层和海马中的表观遗传和转录失调，因为它们是与精神分裂症发病机理密切相关的大脑区域。对信使和microRNA（分别为mRNA和miRNA）进行测序后，在MAM和盐水处理的大鼠之间，在前额叶皮层和海马中发现了差异表达。定性实时聚合酶链反应验证了测序数据。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丰富，包括化学突触传递，认知和炎症反应。同样，DE miRNA的潜在靶基因富含与突触和炎症相关的途径。进一步分析了精神分裂症患者和健康对照者的血液中几种最常见的DE mRNA：DOPA脱羧酶，ret原癌基因，Fc受体样2，干扰素λ受体1和粘液病毒（流感病毒）抗性2。结果表明，这些基因的表达在精神分裂症患者中失调。将这些mRNA结合起来可以充分区分精神分裂症患者和对照组。两者合计，这项研究表明，MAM模型具有在表观遗传和转录水平上复制与精神分裂症有关的海马和前额叶皮层异常的潜力。这些数据也为精神分裂症的诊断和治疗提供了新的靶点。