Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering
Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering
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DOI：
10.1093/brain/awu350
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发表时间：
2015-02-01
期刊：
影响因子：
14.5
通讯作者：
Loeb, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Dachet, Fabien;Bagla, Shruti;Loeb, Jeffrey A.
尽管癫痫与多种异常有关，但究竟为什么某些大脑区域会产生癫痫发作而其他区域则不会，尚不清楚。我们开发了一种使用转录聚类来识别人类癫痫新皮质细胞变化的方法。对 15 名患者体内记录的高峰值和低峰值组织进行配对分析，预测了 11 种细胞特异性变化及其“细胞相互作用组”。这些预测在组织学上得到了验证，揭示了毫米大小的“微病变”以及血管和小胶质细胞的整体增加。使用神经元标记物 NeuN 可以轻松识别更深皮质层中的微病变，显示神经元过程显着减少，并且与浅层中癫痫活动标记 MAPK/CREB 信号传导的附近激活相关。微损伤构成了人类新皮质中一种常见的、未被发现的神经元连接层特异性异常，可能是许多“非损伤”形式的癫痫的原因。这里使用的转录聚类方法可以更广泛地应用于预测其他大脑和复杂组织疾病的细胞差异。
Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders.