未经授权:自闭症谱系障碍(ASD)是一种神经发育障碍,其特征是社交互动不足,沟通和重复,限制性行为,皮层活动支持的功能。鉴于侧腹侧脑室下区(SVZ)对皮质发育的重要性,我们比较了分子,细胞,ASD病例标本中SVZ和相关皮质区域的结构差异以及性别和年龄匹配的未受影响的大脑。
UNASSIGNED:我们对离体死后脑样本使用了磁共振成像(MRI)和扩散束成像,我们通过全基因组亚硫酸氢盐测序(WGBS)进一步分析,流式细胞仪,和RTqPCR。
未经评估:通过MRI,我们观察到背侧SVZ的纤维束造影途径减少,从后腹侧SVZ到岛叶皮质的通路增加,在ASD诊断病例中,相对于未受影响的对照组,岛叶皮质内的皮质厚度可变。在ASD病例中,从岛到岛的远程纤维束造影途径也减少了。基于FACS的细胞分选显示,相对于未受影响的对照,ASD病例的SVZ中的增殖细胞群体增加。SVZ组织的靶向qPCR测定表明,与对照对应物相比,ASD中参与神经元分化和迁移的基因的表达水平显著降低。最后,使用全基因组DNA甲基化分析,我们确定了19个与神经发育相关的基因,函数,和疾病,其中7个以前没有在ASD中描述过,在自闭症SVZ和脑岛标本中,甲基化差异显着。
UNASSIGNED:这些发现提出了一个假设,即神经发育过程中的表观遗传变化改变了增殖的轨迹,迁移,和SVZ的差异化,影响皮质结构和功能,并导致ASD表型。
UNASSIGNED: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.
UNASSIGNED: We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.
UNASSIGNED: Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed
case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD
case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD
case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.
UNASSIGNED: These findings suggest a hypothesis that
epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.