Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?
Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?
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DOI：
10.1523/jneurosci.2323-09.2009
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发表时间：
2009-08-26
期刊：
影响因子：
--
通讯作者：
Friedman A
中科院分区：
文献类型：
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作者：
David Y;Cacheaux LP;Ivens S;Lapilover E;Heinemann U;Kaufer D;Friedman A
局灶性癫痫通常在创伤性、缺血性或感染性脑损伤后发生。虽然癫痫大脑的电活动特征很好，但癫痫发生的机制却知之甚少。我们最近发现，在大鼠新皮层中，血脑屏障（BBB）的长期破坏或新皮层直接暴露于血清衍生的白蛋白导致星形胶质细胞标志物胶质细胞酸性蛋白（GFAP）的快速上调，随后延迟（4-7天内）癫痫灶的发展。我们在癫痫发生的BBB破坏和白蛋白模型中研究了星形胶质细胞在癫痫发生中的作用。我们发现，在用脱氧胆酸（BBB分解）或白蛋白治疗后数小时内，新皮质中星形胶质细胞基因表达发生了类似的、强烈的变化。这些变化预示细胞外谷氨酸和钾的清除能力降低。体外电生理记录证实，暴露于白蛋白后24 h，钾和谷氨酸的活性依赖性蓄积清除率降低。我们使用神经元模型来模拟星形胶质细胞对钾和谷氨酸的摄取减少对兴奋性突触后电位（EPSP）的影响。该模型预测谷氨酸的积累与频率依赖性（>100 Hz）的EPSP易化降低相关，而钾的积累导致频率依赖性（10-50 Hz）和N-甲基-D-天冬氨酸（NMDA）依赖性的突触易化。癫痫发生过程中的体外电生理记录证实了频率依赖性突触易化，导致癫痫样活动。我们的数据表明，转录介导的星形胶质细胞转化早期癫痫。我们认为，由此产生的减少细胞外钾的清除率的基础频率依赖性神经元的超兴奋性和网络同步。
Focal epilepsy often develops following traumatic, ischemic or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid up-regulation of the astrocytic marker, glial fibrillary acidic protein (GFAP), followed by delayed (within 4–7 days) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in-vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on excitatory postsynaptic potentials (EPSPs). The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependant (10–50 Hz) and N-methyl-D-aspartic acid (NMDA)-dependent synaptic facilitation. In-vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependant synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyper-excitability and network synchronization.