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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Anomalous levels of Cl~- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory
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Anomalous levels of Cl~- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory

机译：颞叶癫痫患者海马下支的Cl〜-转运蛋白异常水平使GABA兴奋

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摘要

The mRNA levels of NKCC1, an inwardly directed Na~+, K~+-2Cl~-cotransporter that facilitates the accumulation of intracellular Cl~-, and of KCC2, an outwardly directed K~+-Cl~- cotransporter that extrudes Cl~-, were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients. Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl~-transporters in the TLE subiculum. In parallel experiments, cell membranes isolated from the same TLE-associated brain regions were injected into Xenopus oocytes that rapidly incorporated human GABA_A receptors into their surface membrane. The GABA currents elicited in oocytes injected with membranes from the subiculum had a more depolarized reversal potential (E_(GABA)) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10℃ shifted the GABA-current E_(GABA) more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the E_(GABA) of TL neocortex-injected oocytes. We conclude that the anomalous expression of both Cl~- transporters, KCC1 and NKCC2, in TLE hippocampal subiculum probably causes altered Cl~- transport in the "epileptic" neurons, as revealed in the microtransplanted Xenopus oocytes, and renders GABA aberrantly "exciting," a feature that may contribute to the precipitation of epileptic seizures.
机译：NKCC1（一种向内引导的Na〜+，K〜+ -2Cl--共转运子，促进细胞内Cl〜-的积累）的mRNA水平和KCC2（一种向外引导的K〜+ -Cl〜-共转运蛋白，挤出Cl〜研究人员对来自耐药性颞叶（TL）癫痫病（TLE）患者的手术切除的大脑标本进行了研究。从人类TLE相关脑区提取的mRNA的定量RT-PCR分析显示，与海马固有层或TL新皮层相比，海马下丘脑NKCC1 mRNA上调，而KCC2 mRNA下调。 TLE亚基中Cl〜转运蛋白的异常转录在平行实验中，将从相同的TLE相关脑区域分离的细胞膜注射到非洲爪蟾卵母细胞中，该卵母细胞将人GABA_A受体快速整合到它们的表面膜中。与自海马体或新皮层相比，在注射了来自下丘脑膜的卵母细胞中引起的GABA电流具有更去极化的逆转电位（E_（GABA））。 NKCC1阻断剂布美他尼或温度降低10℃会使从TLE海马下支膜注射的卵母细胞中的GABA电流E_（GABA）更加负向移动，与TL新皮层注射的卵母细胞的E_（GABA）相匹配。我们得出的结论是，在微型海马爪蟾卵母细胞中发现，TLE海马下支路上的Cl〜-转运蛋白KCC1和NKCC2的异常表达可能导致“癫痫”神经元的Cl〜-转运发生改变，并使GABA异常“令人兴奋，可能有助于癫痫发作的发作。

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