Zhang Xueqing, Ibi Masakazu, Haga Ryu, Iwata Kazumi, Matsumoto Misaki, Asaoka Nozomi, Liu Junjie, Katsuyama Masato, Yabe-Nishimura Chihiro
Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:59-66. doi: 10.1016/j.bbrc.2020.11.070. Epub 2020 Dec 10.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic and environmental factors. Among the environmental factors, maternal infection is known as one of the principal risk factors for ASD. On the other hand, postmortem studies suggested the relationship of oxidative stress with ASD etiology. However, the role of oxidative stress in the development of ASD remains unclear. Here, we report the involvement of NOX1/NADPH oxidase, an enzyme generating reactive oxygen species (ROS), in behavioral and anatomical abnormalities in a maternal immune activation (MIA) model. In the MIA model of gestational polyinosinic-polycytidylic acid (poly(I:C)) exposure, increased serum levels of IL-6 were observed in both wild-type (WT) and Nox1-deficient mice (Nox1KO). Following the comparable induction of MIA in the two genotypes, impairment of social preference and defects in motor coordination were observed in WT offspring but not in offspring deficient in Nox1. MIA up-regulated NOX1 mRNA in the cerebral cortex and cerebellum of the fetus but not in the adult offspring. Although the development of cortical neurons was unaffected by MIA in either genotype, the dropout of Purkinje cells in lobule VII of MIA-affected offspring was significantly ameliorated in Nox1KO. Taken together, these results suggested that NOX1/NADPH oxidase plays an essential role in some behavioral phenotypes observed in ASD, possibly by promoting the loss of Purkinje cells in the cerebellum.
自闭症谱系障碍（ASD）是一种由遗传和环境因素引起的神经发育障碍。在环境因素中，母体感染是已知的ASD主要风险因素之一。另一方面，尸检研究表明氧化应激与ASD病因之间存在关联。然而，氧化应激在ASD发展中的作用仍不清楚。在此，我们报告了NOX1/NADPH氧化酶（一种产生活性氧（ROS）的酶）在母体免疫激活（MIA）模型的行为和解剖学异常中的作用。在妊娠期间暴露于聚肌苷酸-聚胞苷酸（poly(I:C)）的MIA模型中，野生型（WT）和Nox1基因敲除小鼠（Nox1KO）的血清IL-6水平均升高。在两种基因型中诱导出相当程度的MIA后，WT后代出现社交偏好受损和运动协调缺陷，而Nox1缺陷的后代则未出现。MIA使胎儿大脑皮层和小脑中的NOX1 mRNA上调，但成年后代中未出现这种情况。尽管两种基因型中皮质神经元的发育均不受MIA影响，但在Nox1KO中，MIA影响的后代小叶VII中浦肯野细胞的缺失明显改善。综上所述，这些结果表明NOX1/NADPH氧化酶在ASD中观察到的一些行为表型中起重要作用，可能是通过促进小脑中浦肯野细胞的丢失。
