Multi-omics analysis suggests enhanced epileptogenesis in theCornu Ammonis3 of the pilocarpine model of mesial temporal lobe epilepsy
Multi-omics analysis suggests enhanced epileptogenesis in theCornu Ammonis3 of the pilocarpine model of mesial temporal lobe epilepsy
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DOI：
10.1002/hipo.23268
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发表时间：
2020-10-10
期刊：
影响因子：
3.5
通讯作者：
Lopes-Cendes, Iscia
中科院分区：
文献类型：
--
作者：
Canto, Amanda M.;Matos, Alexandre H. B.;Lopes-Cendes, Iscia
内侧颞叶癫痫（MTLE）是一种以癫痫发作和内侧颞叶结构的组织病理学异常（主要是海马硬化）为特征的慢性神经系统疾病。本研究采用多组学方法，对毛果芸香碱诱导的MTLE动物模型中海马齿状回（DG）和海马角3（CA 3）的转录和蛋白表达谱进行了研究。我们从毛果芸香碱诱导的Wistar大鼠中分离的激光显微组织中进行了无标记蛋白质组学和RNAseq。我们将DG和CA 3分为背侧和腹侧两个区域，分别进行分析。我们进行了数据集成分析，并评估了丰富的信号通路，以及基于基因本体过程生成的集成网络。我们的研究结果表明，海马DG和CA 3子字段之间的转录组和蛋白质组学的差异。此外，我们的数据表明，癫痫是增强在CA 3区相比，DG，与大多数异常的转录和蛋白质水平发生在CA 3。此外，我们的研究结果表明，在匹鲁卡品模型中的癫痫主要涉及由N-甲基D-天冬氨酸（NMDA）受体介导的兴奋性神经元机制的异常调节，5-羟色胺信号的变化，以及由钙/钙调素依赖性蛋白激酶（CaMK）调节和富含亮氨酸的重复序列激酶2（LRRK 2）/WNT信号通路控制的神经元活性。
Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) andCornu Ammonis3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein kinase (CaMK) regulation and leucine-rich repeat kinase 2 (LRRK2)/WNT signaling pathways.