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Poly(I:C) Challenge Alters Brain Expression of Oligodendroglia-Related Genes of Adult Progeny in a Mouse Model of Maternal Immune Activation.
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2020-06-03 , DOI: 10.3389/fnmol.2020.00115
Xiao-Fan Zhang 1, 2 , Ting Chen 3 , Aifen Yan 4 , Jia Xiao 5, 6 , Yong-Li Xie 6 , Jing Yuan 6 , Pin Chen 5 , Anderson On-Lam Wong 7 , Yang Zhang 3 , Nai-Kei Wong 2, 6
Affiliation  

Background: Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Despite an increasing appreciation that such white matter disconnectivity is linked to social behavior deficits, virtually no etiologically meaningful myelin-related genes have been identified in oligodendrocytes, the key myelinating cells in the CNS, to furnish an account on the causes. The impact of neurodevelopmental perturbations during pregnancy such as maternal immune activation (MIA) on these genes in memory-related neural networks has not been experimentally scrutinized.

Methods: In this study, a mouse model of MIA by the viral dsRNA analog poly(I:C) was employed to mimic the effects of inflammation during pregnancy. Transcriptional expression levels of selected myelin- or oligodendroglia-related genes implicated in schizophrenia or ASD development were analyzed by in situ hybridization (ISH) and quantitative real-time PCR (qRT-PCR) with brain samples from MIA and control groups. The analysis focused on SOX-10 (SRY-related HMG-box 10), MAG (myelin-associated glycoprotein), and Tf (transferrin) expression in the hippocampus and the surrounding memory-related cortical regions in either hemisphere.

Results: Specifically, ISH reveals that in the brain of prenatal poly(I:C)-exposed mouse offspring in the MIA model (gestation day 9), mRNA expression of the genes SOX10, MAG and Tf were generally reduced in the limbic system including the hippocampus, retrosplenial cortex and parahippocampal gyrus on either side of the hemispheres. qRT-PCR further confirms the reduction of SOX10, MAG, and Tf expression in the medial prefrontal cortex, sensory cortex, amygdala, and hippocampus.

Conclusions: Our present results provide direct evidence that prenatal exposure to poly(I:C) elicits profound and long-term changes in transcript level and spatial distribution of myelin-related genes in multiple neocortical and limbic regions, notably the hippocampus and its surrounding memory-related neural networks. Our work demonstrates the potential utility of oligodendroglia-related genes as biomarkers for modeling neurodevelopmental disorders, in agreement with the hypothesis that MIA during pregnancy could lead to compromised white matter connectivity in ASD.



中文翻译:

在母体免疫激活的小鼠模型中,Poly(I:C)挑战改变了成人少儿生殖器官相关基因的大脑表达。

背景:白质连通性的改变,如神经影像学研究中髓鞘和轴突完整性的普遍微观结构变化所证明,已与自闭症谱系障碍(ASD)的发展和相关的神经发育状况(如精神分裂症)有关。尽管人们越来越认识到这种白质分离性与社会行为缺陷有关,但实际上在少突胶质细胞(中枢神经系统的关键髓鞘细胞)中没有发现具有病因学意义的髓磷脂相关基因,以提供原因的信息。尚未对怀孕期间神经发育紊乱(如母体免疫激活(MIA))对记忆相关神经网络中这些基因的影响进行研究。

方法:在这项研究中,通过病毒dsRNA类似物poly(I:C)制成的MIA小鼠模型用于模拟妊娠期炎症的影响。通过与精神分裂症或ASD发育有关的选定的髓鞘或少突胶质细胞相关基因的转录表达水平进行分析原位与来自MIA和对照组的脑样本进行杂交(ISH)和定量实时PCR(qRT-PCR)。分析重点在于SOX-10 (与SRY相关的HMG框10), 美格 (髓磷脂相关糖蛋白),和 f (转铁蛋白)在任一半球的海马及周围记忆相关皮质区域中的表达。

结果:特别是,ISH揭示了在MIA模型(妊娠第9天)的产前暴露于多聚(I:C)的小鼠后代的大脑中,该基因的mRNA表达 SOX10美格f通常在半球两侧的海马系统,脾后皮质和海马旁回的边缘系统中减少。qRT-PCR进一步证实了SOX10美格f 在前额内侧皮层,感觉皮层,杏仁核和海马中表达。

结论:我们目前的结果提供了直接的证据,表明产前暴露于poly(I:C)会在多个新皮层和边缘区域(尤其是海马及其周围的记忆)中引起髓鞘相关基因的转录水平和空间分布发生深远和长期的变化,相关的神经网络。我们的工作证明了少突神经胶质相关基因作为建模神经发育障碍的生物标记物的潜在用途,这与假孕期MIA可能导致ASD中白质连通性受损的假设相符。

更新日期:2020-06-30
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