Potschka H, Krupp E, Ebert U, Gümbel C, Leichtlein C, Lorch B, Pickert A, Kramps S, Young K, Grüne U, Keller A, Welschof M, Vogt G, Xiao B, Worley P F, Löscher W, Hiemisch H
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Neurosci. 2002 Dec;16(11):2157-65. doi: 10.1046/j.1460-9568.2002.02265.x.
Despite an extensive research on the molecular basis of epilepsy, the essential players in the epileptogenic process leading to epilepsy are not known. Gene expression analysis is one strategy to enhance our understanding of the genes contributing to the functional neuronal changes underlying epileptogenesis. In the present study, we used the novel MPSS (massively parallel signature sequencing) method for analysis of gene expression in the rat kindling model of temporal lobe epilepsy. Kindling by repeated electrical stimulation of the amygdala resulted in the differential expression of 264 genes in the hippocampus compared to sham controls. The most strongly induced gene was Homer 1A, an immediate early gene involved in the modulation of glutamate receptor function. The overexpression of Homer 1A in the hippocampus of kindled rats was confirmed by RT-PCR. In order to evaluate the functional implications of Homer 1A overexpression for kindling, we used transgenic mice that permanently overexpress Homer 1A. Immunohistochemical characterization of these mice showed a marked Homer 1A overexpression in glutamatergic neurons of the hippocampus. Kindling of Homer 1A overexpressing mice resulted in a retardation of seizure generalization compared to wild-type controls. The data demonstrate that kindling-induced epileptogenesis leads to a striking overexpression of Homer 1A in the hippocampus, which may represent an intrinsic antiepileptogenic and anticonvulsant mechanism in the course of epileptogenesis that counteracts progression of the disease.
尽管对癫痫的分子基础进行了广泛研究，但导致癫痫的致痫过程中的关键因素仍不清楚。基因表达分析是一种增强我们对参与癫痫发生过程中功能性神经元变化的基因理解的策略。在本研究中，我们使用了新颖的MPSS（大规模平行签名测序）方法来分析颞叶癫痫大鼠点燃模型中的基因表达。与假手术对照组相比，通过反复电刺激杏仁核进行点燃导致海马中264个基因的差异表达。诱导最强的基因是Homer 1A，它是一种参与谷氨酸受体功能调节的即刻早期基因。通过RT-PCR证实了点燃大鼠海马中Homer 1A的过表达。为了评估Homer 1A过表达对点燃的功能影响，我们使用了永久过表达Homer 1A的转基因小鼠。这些小鼠的免疫组织化学特征显示海马谷氨酸能神经元中Homer 1A明显过表达。与野生型对照组相比，过表达Homer 1A的小鼠点燃后癫痫发作的泛化延迟。数据表明，点燃诱导的癫痫发生导致海马中Homer 1A显著过表达，这可能代表癫痫发生过程中的一种内在抗癫痫和抗惊厥机制，可抵消疾病的进展。
