Takahashi Emi, Allan Nina, Peres Rafael, Ortug Alpen, van der Kouwe Andre J W, Valli Briana, Ethier Elizabeth, Levman Jacob, Baumer Nicole, Tsujimura Keita, Vargas-Maya Nauru Idalia, McCracken Trevor A, Lee Rosa, Maunakea Alika K
Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
Front Neurosci. 2023 Feb 3;16:1023665. doi: 10.3389/fnins.2022.1023665. eCollection 2022.
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.
We used magnetic resonance imaging (MRI) and diffusion tractography on postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.
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.
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.
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、沟通以及重复、受限行为存在缺陷，这些特征由皮质活动所支持。鉴于侧脑室室下区（SVZ）对皮质发育的重要性，我们比较了ASD病例标本与性别和年龄匹配的未受影响大脑标本中SVZ及相关皮质区域的分子、细胞和结构差异。
我们对死后脑样本进行了磁共振成像（MRI）和弥散张量成像，随后通过全基因组亚硫酸氢盐测序（WGBS）、流式细胞术和逆转录定量聚合酶链反应（RT qPCR）进行进一步分析。
通过MRI，我们观察到，与未受影响的对照组相比，被诊断为ASD的病例中，从背侧SVZ发出的弥散张量成像通路减少，从腹侧后SVZ到岛叶皮质的通路增加，且岛叶皮质内的皮质厚度存在差异。ASD病例中，与岛叶相连的长距离弥散张量成像通路也减少。基于流式细胞术的细胞分选显示，与未受影响的对照组相比，ASD病例SVZ中增殖细胞群体增加。对SVZ组织进行的靶向qPCR分析表明，与对照组相比，ASD中参与神经元分化和迁移的基因表达水平显著降低。最后，通过全基因组DNA甲基化分析，我们鉴定出19个与神经发育、功能和疾病相关的基因，其中7个此前未在ASD中被描述，这些基因在自闭症患者的SVZ和岛叶标本中存在显著的甲基化差异。
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SVZ中增殖、迁移和分化的轨迹，影响皮质结构和功能，从而导致ASD表型。
