Glial cells are now recognized as active communication partners in the central nervous system, and this new perspective has rekindled the question of their role in pathology. In the present study we analysed functional properties of astrocytes in hippocampal specimens from patients with mesial temporal lobe epilepsy without (n = 44) and with sclerosis (n = 75) combining patch clamp recording, K⁺ concentration analysis, electroencephalography/video-monitoring, and fate mapping analysis. We found that the hippocampus of patients with mesial temporal lobe epilepsy with sclerosis is completely devoid of bona fide astrocytes and gap junction coupling, whereas coupled astrocytes were abundantly present in non-sclerotic specimens. To decide whether these glial changes represent cause or effect of mesial temporal lobe epilepsy with sclerosis, we developed a mouse model that reproduced key features of human mesial temporal lobe epilepsy with sclerosis. In this model, uncoupling impaired K⁺ buffering and temporally preceded apoptotic neuronal death and the generation of spontaneous seizures. Uncoupling was induced through intraperitoneal injection of lipopolysaccharide, prevented in Toll-like receptor4 knockout mice and reproduced in situ through acute cytokine or lipopolysaccharide incubation. Fate mapping confirmed that in the course of mesial temporal lobe epilepsy with sclerosis, astrocytes acquire an atypical functional phenotype and lose coupling. These data suggest that astrocyte dysfunction might be a prime cause of mesial temporal lobe epilepsy with sclerosis and identify novel targets for anti-epileptogenic therapeutic intervention.

中文翻译：

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星形胶质细胞解偶联是人类颞叶癫痫的原因

胶质细胞现在被认为是中枢神经系统中的活跃交流伙伴，这种新观点重新点燃了它们在病理学中的作用的问题。在本研究中，我们结合膜片钳记录，K ⁺浓度分析，脑电图/视频监控，分析了没有（n = 44）和有硬化（n = 75）的中颞叶癫痫患者海马标本中星形胶质细胞的功能特性，和命运映射分析。我们发现患有颞叶内侧癫痫并硬化的患者的海马体完全没有诚意星形胶质细胞和间隙连接偶联，而非硬化性标本中大量存在偶联的星形胶质细胞。为了确定这些神经胶质变化是代表硬化性中颞叶癫痫的病因还是结果，我们开发了一种小鼠模型，该模型复制了人类硬化性颞中叶癫痫的关键特征。在该模型中，解偶联削弱了K ⁺缓冲，并在时间上先于凋亡神经元死亡和自然发作。通过腹膜内注射脂多糖诱导解偶联，在Toll样受体4基因敲除小鼠中预防并原位复制通过急性细胞因子或脂多糖孵育。命运图谱证实，在患有硬化的中颞叶癫痫的过程中，星形胶质细胞获得非典型功能表型并失去偶联。这些数据表明星形胶质细胞功能障碍可能是硬化性中颞叶癫痫的主要原因，并确定了抗癫痫治疗干预的新靶点。