Department of Neuroscience.
Center for Cell and Gene Therapy.
J Clin Invest. 2020 May 1;130(5):2286-2300. doi: 10.1172/JCI133316.
Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor-driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.
癫痫发作通常预示着神经胶质瘤的临床出现或出现在后期。剖析其在脑恶性肿瘤中的精确演变和细胞发病机制，可以为这些高度耐药性癫痫的分期治疗提供信息。在免疫缺陷异种移植模型中的研究已经确定了局部中间神经元的丧失和过多的胶质谷氨酸释放是导致网络去抑制的主要因素，但在免疫活性脑内，肿瘤周围微环境中的过度兴奋如何演变尚不清楚。我们通过在子宫内缺失关键肿瘤抑制基因在 WT 小鼠中生成神经胶质瘤，并通过体内电生理学和 GCAMP7 钙成像对肿瘤浸润期间的皮质癫痫发生进行连续监测，揭示了从过度兴奋到癫痫发作的可重复进展。早在癫痫发作之前，与抑制性细胞及其保护支架的丧失、胶质谷氨酸反向转运蛋白 xCT 表达的增加和反应性星形胶质细胞增生同时发生，我们检测到局部 Iba1+小胶质细胞炎症，其强度增加，后来甚至扩展到肿瘤边界之外。迄今为止尚未被认识到的皮质扩散性去极化事件可能是短暂神经功能缺损的一种机制。早期阻断胶质 xCT 活性可抑制后期癫痫发作，通过删除 MapT 减少宿主大脑兴奋性可抑制癫痫发生和癫痫发作的分子标志物。我们的研究证实了异种移植肿瘤驱动的病理生物学，并在遗传上可处理的、免疫活性的神经胶质瘤小鼠模型中揭示了肿瘤相关癫痫发生的早期和晚期成分，从而能够复杂地剖析肿瘤与宿主致病癫痫机制。
