Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity
Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity
复制标题
神经胶质谷氨酸转运蛋白的遗传和药理学操作不会改变感染诱发的癫痫发作活动
DOI：
10.1016/j.expneurol.2019.04.010
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发表时间：
2019
影响因子：
5.3
通讯作者：
Wilcox Karen S.
中科院分区：
文献类型：
--
作者：
Loewen Jaycie L.;Albertini Giulia;Dahle E. Jill;Sato Hideyo;Smolders Ilse J.;Massie Ann;Wilcox Karen S.
神经胶质转运蛋白对谷氨酸跨膜运动的贡献已被确定为抗癫痫治疗的潜在靶点。两个这样的谷氨酸转运体，GLT-1和系统xc−，在神经胶质细胞上表达，并且它们的表达和功能的调节已被确定为可以在脑损伤模型中减少癫痫发作、神经元损伤和神经胶质增生的手段。虽然GLT-1负责大脑中大部分谷氨酸的摄取，但系统xc−在细胞外间隙中释放谷氨酸以交换胱氨酸，并代表海马细胞外谷氨酸的主要来源。使用Theiler小鼠脑脊髓炎病毒（TMEV）病毒诱导的癫痫模型，我们采取了两种经过充分研究的方法，一种是药理学方法，一种是遗传学方法，来研究GLT-1和系统xc−在TMEV诱导的病理学中的潜在作用。我们的研究结果表明，我们用来调节这些神经胶质转运蛋白的方法，虽然在其他模型中有效，但不足以减少TMEV感染小鼠的行为癫痫发作的数量或严重程度。然而，xc-系统的特异性亚基xCT的基因敲除可能具有细胞效应，因为我们观察到TMEV引起的神经元损伤轻微减少，海马CA 1区星形胶质细胞增生增加。此外，xCT敲除导致皮质中GLT-1表达选择性增加。这些发现对TMEV模型的表征以及未来发现新的有效的抗癫痫药物的努力具有重要意义。
The contribution of glial transporters to glutamate movement across the membrane has been identified as a potential target for anti-seizure therapies. Two such glutamate transporters, GLT-1 and system xc−, are expressed on glial cells, and modulation of their expression and function have been identified as a means by which seizures, neuronal injury, and gliosis can be reduced in models of brain injury. While GLT-1 is responsible for the majority of glutamate uptake in the brain, system xc−releases glutamate in the extracellular cleft in exchange for cystine and represents as such the major source of hippocampal extracellular glutamate. Using the Theiler's Murine Encephalomyelitis Virus (TMEV) model of viral-induced epilepsy, we have taken two well-studied approaches, one pharmacological, one genetic, to investigate the potential role(s) of GLT-1 and system xc−in TMEV-induced pathology. Our findings suggest that the methods we utilized to modulate these glial transporters, while effective in other models, are not sufficient to reduce the number or severity of behavioral seizures in TMEV-infected mice. However, genetic knockout of xCT, the specific subunit of system xc−, may have cellular effects, as we observed a slight decrease in neuronal injury caused by TMEV and an increase in astrogliosis in the CA1 region of the hippocampus. Furthermore, xCT knockout caused an increase in GLT-1 expression selectively in the cortex. These findings have significant implications for both the characterization of the TMEV model as well as for future efforts to discover novel and effective anti-seizure drugs.