Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder
Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder
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DOI：
10.1016/j.neuint.2017.07.004
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发表时间：
2018-10-01
影响因子：
4.2
通讯作者：
Nomura, Yasuyuki
中科院分区：
文献类型：
--
作者：
Kawada, Koichi;Mimori, Seisuke;Nomura, Yasuyuki
神经发育障碍是一种先天性缺陷，阻碍中枢神经系统的生长发育。这些障碍包括自闭症谱系障碍（ASD）和注意力缺陷/多动障碍（精神障碍诊断与统计手册-5）。自闭症谱系障碍是由基因缺陷和染色体重复引起的。尽管有许多关于ASD的报道，但致病机制尚不清楚。预防和治疗ASD的最佳方法也不清楚。其他研究报道内质网应激参与神经退行性疾病的发病机制。在本研究中，我们利用雄性ICR小鼠研究了内质网应激条件和ASD小鼠模型中的神经元成熟。采用丙戊酸（VPA）孕鼠注射方法建立ASD小鼠模型。经vpa处理的母鼠所生的后代作为ASD模型小鼠进行实验。ASD模型小鼠的大脑皮层和海马处于高内质网应激状态。ASD模型小鼠大脑皮层Hes1和Pax6 mRNA表达水平降低，海马无明显变化。此外，大脑皮层Math1 mRNA水平升高。内质网应激抑制E14.5小鼠大脑皮层原代培养的树突和轴突延伸。此外，通过同样的方法，从ASD模型小鼠的大脑皮层中提取的原代培养物可以抑制树突的生长。这些结果提示内质网应激可能诱导雄性ICR小鼠ASD模型小鼠胚胎期大脑皮层异常神经元成熟。因此，内质网应激可能参与ASD的发病机制。(C) 2017 Elsevier Ltd.版权所有。
Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice.An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method.These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD. (C) 2017 Elsevier Ltd. All rights reserved.