Blümcke I, Becker A J, Klein C, Scheiwe C, Lie A A, Beck H, Waha A, Friedl M G, Kuhn R, Emson P, Elger C, Wiestler O D
Department of Neuropathology, University of Bonn Medical Center, Germany.
J Neuropathol Exp Neurol. 2000 Jan;59(1):1-10. doi: 10.1093/jnen/59.1.1.
Aberrant axonal reorganization and altered distribution of neurotransmitter receptor subtypes have been proposed as major pathogenic mechanisms for hippocampal hyperexcitability in chronic temporal lobe epilepsies (TLE). Recent data point to excitatory class I metabotropic glutamate receptors (mGluR1 and mGluR5) as interesting candidates. Here, we have analyzed the hippocampal distribution and mRNA expression of mGluR1 and mGluR5 in two rat models of limbic seizures, i.e. electrical kindling and intraperitoneal kainate injections, as well as in human TLE. Quantitative RT-PCR analysis detected a significant increase of hippocampal mGluR1 gene transcript levels in kainate treated and kindled rats. In addition, microdissected hippocampal tissue samples localized this increase to the dentate gyrus. Using immunohistochemistry with mGluR1alpha subtype specific antibodies, increased labeling was observed within the dentate gyrus molecular layer (DG-ML). A similar pattern of increased mGluR1alpha neuropil staining was found within the DG-ML of epilepsy patients (n = 42) compared with peritumoral hippocampus specimens obtained from nonepileptic patients (biopsy controls, n = 3). This increase was detected in TLE patients with segmental hippocampal cell loss, as well as in TLE patients with focal lesions but no histopathological alterations of the hippocampus. In contrast, mGluR5 immunoreactivity and mRNA expression were not significantly altered in the DG-ML. Our data demonstrate a striking regional induction of mGluR1alpha in the hippocampal dentate gyrus of experimental animals with limbic seizures as well as in human patients with chronic, intractable TLE. This increase corresponds to functional alterations of class I mGluRs observed in seizure models and may significantly contribute to hippocampal hyperexcitability in focal human epilepsies.
异常的轴突重组和神经递质受体亚型分布改变被认为是慢性颞叶癫痫（TLE）中海马兴奋性过高的主要致病机制。最近的数据表明兴奋性I类代谢型谷氨酸受体（mGluR1和mGluR5）是有趣的候选者。在此，我们分析了边缘性癫痫的两种大鼠模型（即电点燃和腹腔注射红藻氨酸）以及人类TLE中mGluR1和mGluR5的海马分布和mRNA表达。定量逆转录聚合酶链反应（RT-PCR）分析检测到红藻氨酸处理和点燃的大鼠海马mGluR1基因转录水平显著增加。此外，显微切割的海马组织样本将这种增加定位到齿状回。使用mGluR1α亚型特异性抗体进行免疫组织化学分析，在齿状回分子层（DG-ML）内观察到标记增加。与从非癫痫患者获得的瘤周海马标本（活检对照，n = 3）相比，在癫痫患者（n = 42）的DG-ML内发现了类似的mGluR1α神经纤维染色增加模式。在海马节段性细胞丢失的TLE患者以及有局灶性病变但海马无组织病理学改变的TLE患者中均检测到这种增加。相比之下，DG-ML中的mGluR5免疫反应性和mRNA表达没有显著改变。我们的数据表明，在患有边缘性癫痫的实验动物以及患有慢性顽固性TLE的人类患者的海马齿状回中，mGluR1α有显著的区域诱导。这种增加与癫痫模型中观察到的I类mGluR的功能改变相对应，可能显著导致局灶性人类癫痫中海马兴奋性过高。
