Department of Pharmacology and Toxicology, University of Utah, USA; Interdepartmental Program in Neuroscience, University of Utah, USA.
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Belgium.
Exp Neurol. 2019 Aug;318:50-60. doi: 10.1016/j.expneurol.2019.04.010. Epub 2019 Apr 22.
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 x, 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 x 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 x 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 x, 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.
胶质细胞转运体在跨膜谷氨酸转运中的作用已被确定为抗癫痫治疗的潜在靶点。两种谷氨酸转运体，GLT-1 和系统 x，在神经胶质细胞上表达，调节其表达和功能已被确定为减少脑损伤模型中癫痫发作、神经元损伤和神经胶质增生的一种手段。虽然 GLT-1 负责大脑中大部分谷氨酸的摄取，但系统 x 在细胞外裂隙中释放谷氨酸，以换取胱氨酸，因此是海马体细胞外谷氨酸的主要来源。我们使用 Theiler's 鼠脑脊髓炎病毒（TMEV）病毒诱导的癫痫模型，采用了两种经过充分研究的方法，一种是药理学方法，另一种是遗传学方法，来研究 GLT-1 和系统 x 在 TMEV 诱导的病理中的潜在作用。我们的研究结果表明，我们用于调节这些胶质转运体的方法，虽然在其他模型中有效，但不足以减少 TMEV 感染小鼠的行为性癫痫发作的数量或严重程度。然而，xCT 的基因敲除，即系统 x 的特定亚基，可能具有细胞效应，因为我们观察到 TMEV 引起的神经元损伤略有减少，以及海马体 CA1 区的星形胶质增生增加。此外，xCT 敲除选择性地增加了皮质中的 GLT-1 表达。这些发现对 TMEV 模型的特征以及未来发现新型有效抗癫痫药物的努力都具有重要意义。
