Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.

中文翻译：

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瘢痕形成肿瘤相关星形胶质细胞的钾和谷氨酸转运受损。

无端复发性癫痫发作是一种严重的合并症，影响了大多数患有神经胶质瘤的患者，这是一种由恶性神经胶质细胞组成的原发性脑肿瘤。导致复发性自发性癫痫发作的细胞机制包括兴奋性神经递质谷氨酸从神经胶质瘤释放到细胞外空间。在生理条件下，星形胶质细胞表达两种高亲和力的谷氨酸转运蛋白 Glt-1 和 Glast，它们负责去除多余的细胞外谷氨酸。在神经系统疾病或脑损伤的情况下，星形胶质细胞变得反应性，这会对神经元功能产生负面影响，导致过度兴奋和/或死亡。使用电生理学、免疫组织化学、荧光原位杂交、在人和小鼠神经胶质瘤的不同原位异种移植物和同种异体移植物模型中进行蛋白质印迹和蛋白质印迹分析，我们发现瘤周星形胶质细胞表现出星形胶质细胞瘢痕形成，其特征是增殖、细胞肥大、过程伸长以及 GFAP 和 pSTAT3 增加。总体而言，瘤周反应性星形胶质细胞的谷氨酸和钾吸收显着减少，谷氨酰胺合成酶活性降低。一部分瘤周星形胶质细胞表现出去极化的静息膜电位，进一步导致钾和谷氨酸稳态降低。这些变化可能有助于肿瘤周围神经元过度兴奋和兴奋性毒性死亡的传播。细胞肥大、过程延长、GFAP 和 pSTAT3 增加。总体而言，瘤周反应性星形胶质细胞的谷氨酸和钾吸收显着减少，谷氨酰胺合成酶活性降低。一部分瘤周星形胶质细胞表现出去极化的静息膜电位，进一步导致钾和谷氨酸稳态降低。这些变化可能有助于肿瘤周围神经元过度兴奋和兴奋性毒性死亡的传播。细胞肥大、过程延长、GFAP 和 pSTAT3 增加。总体而言，瘤周反应性星形胶质细胞的谷氨酸和钾摄取显着减少，谷氨酰胺合成酶活性降低。一部分瘤周星形胶质细胞表现出去极化的静息膜电位，进一步导致钾和谷氨酸稳态降低。这些变化可能有助于肿瘤周围神经元过度兴奋和兴奋性毒性死亡的传播。进一步降低钾和谷氨酸稳态。这些变化可能有助于肿瘤周围神经元过度兴奋和兴奋性毒性死亡的传播。进一步降低钾和谷氨酸稳态。这些变化可能有助于肿瘤周围神经元过度兴奋和兴奋性毒性死亡的传播。