Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody mouse model.
Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody mouse model.
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DOI：
10.1038/s41380-021-01215-w
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发表时间：
2021-12
影响因子：
11
通讯作者：
Van de Water J
中科院分区：
文献类型：
--
作者：
Bruce MR;Jones KL;Vernon AC;Silverman JL;Crawley JN;Ellegood J;Lerch JP;Van de Water J
免疫球蛋白G（IgG）的自身抗体反应的胎儿脑蛋白的母亲与ASD的儿童已被描述的几个团体。为了了解它们的病理意义，我们利用来自人自身抗体反应模式的肽表位开发了母体自身抗体相关ASD（MAR-ASD）的小鼠模型。产前暴露于显著的母体自身抗体的雄性和雌性后代在青少年和成年时表现出社会互动的强烈缺陷和重复的自我修饰行为增加。在本研究中，通过6个月大时的高分辨率离体磁共振成像（MRI）评估了成人MAR-ASD和对照后代的神经解剖学差异。有趣的是，MAR-ASD小鼠显示出显著更大的总脑体积，并且在检查的159个区域中，发现31个在FDR <5%时绝对体积（mm 3）显著不同。具体而言，在MAR-ASD动物中，几个白色物质束、皮质区域和基底核结构的绝对体积显著增加。这些现象在很大程度上是由雌性MAR-ASD后代驱动的，因为在雄性MAR-ASD小鼠的绝对或相对区域体积中没有观察到显著差异。然而，结构协方差分析表明，在雄性和雌性MAR-ASD小鼠的脑容量的网络水平的去极化。此外，行为数据的初步相关性分析表明，MAR-ASD小鼠许多脑区的体积增加与性别特异性方式的社会互动和重复性自我梳理行为相关。这些结果表明，与对照组相比，产前暴露于MAR-ASD自身抗体的后代在大脑大小、区域关系和行为方面具有显著的性别特异性影响。
Immunoglobulin G (IgG) autoantibodies reactive to fetal brain proteins in mothers of children with ASD have been described by several groups. To understand their pathologic significance, we developed a mouse model of maternal autoantibody related ASD (MAR-ASD) utilizing the peptide epitopes from human autoantibody reactivity patterns. Male and female offspring prenatally exposed to the salient maternal autoantibodies displayed robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults. In the present study, neuroanatomical differences in adult MAR-ASD and control offspring were assessed via high-resolution ex vivo magnetic resonance imaging (MRI) at 6 months of age. Of interest, MAR-ASD mice displayed significantly larger total brain volume and of the 159 regions examined, 31 were found to differ significantly in absolute volume (mm3) at an FDR of <5%. Specifically, the absolute volumes of several white matter tracts, cortical regions, and basal nuclei structures were significantly increased in MAR-ASD animals. These phenomena were largely driven by female MAR-ASD offspring, as no significant differences were seen with either absolute or relative regional volume in male MAR-ASD mice. However, structural covariance analysis suggests network-level desynchronization in brain volume in both male and female MAR-ASD mice. Additionally, preliminary correlational analysis with behavioral data relates that volumetric increases in numerous brain regions of MAR-ASD mice were correlated with social interaction and repetitive self-grooming behaviors in a sex-specific manner. These results demonstrate significant sex-specific effects in brain size, regional relationships, and behavior for offspring prenatally exposed to MAR-ASD autoantibodies relative to controls.
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