Maternal Immune Activation in a Genetic Mouse Model of ASD

 描述(由申请人提供)：自闭症谱系障碍(ASD)是一种多样化的障碍，很可能是由早期发育过程中的基因改变和环境侮辱引起的。研究表明，孕期母体免疫激活(MIA)与ASD风险增加之间存在关联。最近发展的孕期暴露于母体免疫激活(MIA)的小鼠模型显示，受到攻击的后代表现出与ASD相关的行为受损，并表现出免疫蛋白水平的变化。在理解免疫状态改变如何与ASD风险基因相互作用导致行为受损方面存在着显著的差距。在这里，我们将检验MHC1蛋白调节改变是MIA和ASD遗传风险因素趋同的机制这一假设。具体地说，我们将研究MeCP2的突变是如何与MIA相互作用的。MeCP2是导致Rett综合征的一个基因，也与非Rett ASD病例有关。我们将结合相关大脑回路中的行为、分子、电生理和突触体内成像分析，确定改变的MeCP2水平和MIA如何汇聚到导致行为和神经病理改变的结果。

 DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a diverse disorder that is likely to be caused by a combination of genetic alterations and environmental insult during early development. Studies demonstrate an association between maternal immune activation (MIA) during pregnancy and an increased risk for ASD. Recent development of mouse models for prenatal exposure to maternal immune activation (MIA) show that the challenged offspring demonstrate impaired behaviors relevant to ASD as well as exhibit altered levels of immune proteins. A significant gap exists in understanding how altered immune state interacts with ASD risk genes to result in impaired behaviors. Here we will test the hypothesis altered regulation of MHC1 proteins is a mechanism of convergence for MIA and ASD genetic risk factors. Specifically, we will examine how mutations in mecp2, a gene responsible for the Rett syndrome and also associated with non-Rett ASD cases, interact with MIA. We will, combine behavioral, molecular, electrophysiological and synaptic in vivo imaging analyses in relevant brain circuits to determine how altered Mecp2 levels and MIA converge to results in altered behavior and neuropathology.