PDF(Pubmed)
Abstract：
Seizures are generally associated with epilepsy but may also be a symptom of many other neurological conditions. A hallmark of a seizure is the intensity of the local neuronal activation, which can drive large-scale gene transcription changes. Such changes in the transcriptional profile likely alter neuronal function, thereby contributing to the pathological process. Therefore, there is a strong clinical imperative to characterize how gene expression is changed by seizure activity. To this end, we developed a simplified ex vivo technique for studying seizure-induced transcriptional changes. We compared the RNA sequencing profile in mouse neocortical tissue with up to 3 h of epileptiform activity induced by 4-aminopyridine (4AP) relative to control brain slices not exposed to the drug. We identified over 100 genes with significantly altered expression after 4AP treatment, including multiple genes involved in MAPK, TNF, and neuroinflammatory signaling pathways, all of which have been linked to epilepsy previously. Notably, the patterns in male and female brain slices were almost identical. Various immediate early genes were among those showing the largest upregulation. The set of down-regulated genes included ones that might be expected either to increase or to decrease neuronal excitability. In summary, we found the seizure-induced transcriptional profile complex, but the changes aligned well with an analysis of published epilepsy-associated genes. We discuss how simple models may provide new angles for investigating seizure-induced transcriptional changes.
摘要：
癫痫发作通常与癫痫有关，但也可能是许多其他神经系统疾病的症状。癫痫发作的标志是局部神经元激活的强度，这可以驱动大规模的基因转录变化。转录谱的这种变化可能会改变神经元功能，从而有助于病理过程。因此,有一个强有力的临床必要性来描述基因表达是如何通过癫痫发作活动而改变的。为此,我们开发了一种简化的离体技术，用于研究癫痫引起的转录变化。我们比较了相对于未暴露于药物的对照脑切片，由4-氨基吡啶（4AP）诱导的长达3小时的癫痫样活性的小鼠新皮质组织中的RNA测序谱。我们鉴定了超过100个基因在4AP处理后表达显著改变，包括参与MAPK的多个基因，TNF,和神经炎症信号通路，所有这些以前都与癫痫有关。值得注意的是,男性和女性大脑切片的模式几乎相同。各种即时早期基因是显示最大上调的基因之一。该组下调的基因包括可能预期增加或降低神经元兴奋性的基因。总之,我们发现了癫痫诱导的转录谱复合物，但是这些变化与已发表的癫痫相关基因的分析吻合得很好。我们讨论了简单的模型如何为研究癫痫发作引起的转录变化提供新的角度。重要性陈述已经确定,强神经元激活导致大规模转录组变化。了解这个过程在癫痫中特别重要，其特征是阵发性病理性放电。然而,体内活动模式的复杂性在解释转录变化方面存在许多困难。相比之下,离体癫痫发作模型提供了更好的实验控制和活动模式的定量，福利影响较低。重要的是,我们现在表明，这些模型也复制了以前在慢性人类和动物癫痫中报道的转录模式，从而验证它们在这类研究中的使用。
