Astrocyte uncoupling as a cause of human temporal lobe epilepsy
Astrocyte uncoupling as a cause of human temporal lobe epilepsy
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DOI：
10.1093/brain/awv067
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发表时间：
2015-05-01
期刊：
影响因子：
14.5
通讯作者：
Steinhaeuser, Christian
中科院分区：
文献类型：
--
作者：
Bedner, Peter;Dupper, Alexander;Steinhaeuser, Christian
神经胶质细胞现在被认为是中枢神经系统中活跃的通讯伙伴，这一新的观点重新引发了他们在病理学中的作用问题。在本研究中，我们分析了海马标本星形胶质细胞的功能特性，从内侧颞叶癫痫患者没有（n = 44）和硬化症（n = 75）结合膜片钳记录，K+浓度分析，脑电图/视频监控，和命运映射分析。我们发现，内侧颞叶癫痫硬化患者的海马是完全没有真正的星形胶质细胞和缝隙连接耦合，而耦合的星形胶质细胞大量存在于非硬化标本。为了确定这些胶质细胞的变化是否代表了内侧颞叶癫痫伴硬化的原因或影响，我们开发了一种小鼠模型，该模型再现了人类内侧颞叶癫痫伴硬化的关键特征。在这个模型中，解偶联受损的K+缓冲和时间提前凋亡神经元死亡和自发性癫痫发作的产生。通过腹腔注射脂多糖诱导解偶联，在Toll样受体4敲除小鼠中阻止解偶联，并通过急性细胞因子或脂多糖孵育原位再现解偶联。命运映射证实，在内侧颞叶癫痫硬化的过程中，星形胶质细胞获得一个非典型的功能表型和失去耦合。这些数据表明，星形胶质细胞功能障碍可能是内侧颞叶癫痫硬化的主要原因，并确定新的抗癫痫治疗干预的目标。
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.