Investigate the role of the immune system in modulating motor behavior in a maternal immune activation mouse model of autism spectrum disorder

研究免疫系统在调节自闭症谱系障碍母体免疫激活小鼠模型运动行为中的作用

• 批准号: 22KJ3080
• 负责人: Mi Yang
• 金额: $ 1.09万
• 依托单位: Okinawa Institute of Science and Technology Graduate University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2023
• 资助国家: 日本
• 起止时间: 2023-03-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22KJ3080/
• 关键词: Neuroimmunity; Cerebellum; Neurodevelopment; Autism

Maternal immune activation (MIA) triggered by viral infection during pregnancy induces developmental defects in the fetal cerebral cortex dependent on the Th17/IL-17 pathway, leading to autism spectrum disorder (ASD)-like symptoms. However, the impact of MIA on cerebellum, the brain structure most constantly found abnormal in ASD, is far from clear.The main goal of this project is to provide evidence that MIA interrupts offspring cerebellar development through a specific maternal cytokine signaling and helps to better characterize cerebellar neuropathology in human ASD.Here we found that MIA impairs murine fetal cerebellum development. MIA induces developmental alterations of excitatory cerebellar nuclei excitatory neurons (eCNs) in the fetal cerebellum, both in the mid and late stages of pregnancy.Importantly, the administration of Interferon beta (IFN-β), a major cytokine produced in MIA, into pregnant mice decreases eCNs in the fetal cerebellum. These data suggest that MIA-mediated upregulation of IFN-β leads to defective cerebellar nuclei development, providing new insights into the association of abnormal cytokine signaling in the cerebellum with ASD. In the future, these finds could stimulate further studies aimed at better understanding the immune-neural interaction, which may ultimately inform the development of strategies to reduce the adverse effects of MIA on the fetal cerebellum.

妊娠期病毒感染引发的母体免疫激活（MIA）可诱导依赖于Th 17/IL-17通路的胎儿大脑皮层发育缺陷，导致自闭症谱系障碍（ASD）样症状。然而，MIA对小脑的影响，在ASD中最常发现的异常的脑结构，是远不清楚的。本项目的主要目标是提供证据，MIA通过特定的母体细胞因子信号传导中断后代小脑发育，并有助于更好地描述人类ASD小脑神经病理学。MIA可诱导胎鼠小脑兴奋性小脑核兴奋性神经元（eCN）的发育改变，尤其是在妊娠中晚期，给予MIA产生的主要细胞因子β-干扰素（IFN-β）可减少胎鼠小脑eCN的数量。这些数据表明，MIA介导的IFN-β上调导致小脑核发育缺陷，为小脑中异常细胞因子信号传导与ASD的关联提供了新的见解。在未来，这些发现可以刺激进一步的研究，旨在更好地了解免疫-神经相互作用，这可能最终为减少MIA对胎儿小脑的不良影响的策略的发展提供信息。

项目成果

Analysis of defects in fetal cerebellar development and function caused by maternal immune activation

母体免疫激活导致胎儿小脑发育及功能缺陷分析

• 发表时间: 2022
• 作者: Huang Tsung-Yen;Hirota Masato;Sasaki Daiki;Kalra Rajkumar Singh;Chien Hsiao-Chiao;Tamai Miho;Sarkar Shukla;Mi Yang;Miyagi Mio;Seto Yu;Ishikawa Hiroki;Yang Mi
• 通讯作者: Yang Mi

Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity

• DOI: 10.1016/j.celrep.2023.112205
• 发表时间: 2023-02-28
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Huang，Tsung-Yen;Hirota，Masato;Ishikawa，Hiroki
• 通讯作者: Ishikawa，Hiroki