Patches of disorganization in the neocortex of children with autism.
Patches of disorganization in the neocortex of children with autism.
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DOI：
10.1056/nejmoa1307491
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发表时间：
2014-03-27
期刊：
影响因子：
--
通讯作者：
Courchesne E
中科院分区：
文献类型：
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作者：
Stoner R;Chow ML;Boyle MP;Sunkin SM;Mouton PR;Roy S;Wynshaw-Boris A;Colamarino SA;Lein ES;Courchesne E
自闭症涉及早期大脑过度生长和功能障碍，这在前额皮质最为明显。病理分析表明，自闭症儿童前额叶皮层神经元过多是产前发育障碍的信号，可能伴随着异常的细胞类型和层流发育。为了系统地检查自闭症发病后早期的新皮层结构，我们使用RNA原位杂交和一组层和细胞类型特异性分子标记来显示皮层微观结构的表型。我们分析了神经元和胶质细胞的标记，以及与自闭症风险有关的基因，这些标记来自于自闭症儿童和2至15岁之间未受影响的儿童的死后样本，包括前额叶、颞叶和枕叶的新皮质组织。我们在11名自闭症儿童中的10名和11名正常儿童中的1名的前额叶和颞叶皮质组织中观察到局灶性斑块异常的层状细胞结构和神经元皮质紊乱，但没有胶质细胞。我们观察到在斑块中最不正常的细胞类型和最受病理特征影响的层之间的病例异质性。所有皮质层均未幸免，第4层和第5层异常表达最明显。层标记的三维重建确定了斑块的焦点几何形状和大小。在这个小型的探索性研究中，我们发现大多数自闭症儿童的皮质层结构存在局灶性破坏。我们的数据支持在产前发育阶段层形成和层特异性神经元分化可能失调。（由西蒙斯基金会和其他机构资助。）
Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type– specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.)