GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii.
GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii.
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DOI：
10.1371/journal.ppat.1005643
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发表时间：
2016-06
期刊：
影响因子：
6.7
通讯作者：
Wilson EH
中科院分区：
文献类型：
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作者：
David CN;Frias ES;Szu JI;Vieira PA;Hubbard JA;Lovelace J;Michael M;Worth D;McGovern KE;Ethell IM;Stanley BG;Korzus E;Fiacco TA;Binder DK;Wilson EH
中枢神经系统的免疫特权性质使其易受慢性和潜伏性感染的影响。关于终身脑感染以及炎症对宿主神经系统健康的影响，人们知之甚少。弓形虫是一种寄生虫，可以感染任何哺乳动物的有核细胞，全球平均血清阳性率为30%。弓形虫感染的特征是脑神经元内终身存在寄生虫包囊，需要有能力的免疫系统来防止寄生虫再激活和脑炎。在免疫功能正常的个体中，弓形虫感染在很大程度上是无症状的，然而最近的许多研究表明与某些神经退行性疾病和精神疾病有很强的相关性。在这里，我们证明了一个显着减少的主要星形胶质细胞谷氨酸转运蛋白，GLT-1，感染弓形虫。在感染过程中使用鼠额叶皮层的微透析，观察到细胞外谷氨酸浓度的显著增加。与谷氨酸失调一致，神经元的分析揭示了形态学的变化，包括树突棘，VGlut1和NeuN免疫反应性的减少。此外，行为测试和EEG记录指出神经元输出的显著变化。最后，神经元连接的这些变化依赖于感染诱导的GLT-1下调，因为用β-内酰胺抗生素头孢曲松治疗，挽救了细胞外谷氨酸浓度、神经元病理和功能。总之，这些数据表明，在感染T。在弓形虫感染后，星形胶质细胞对谷氨酸的精细调节被破坏，并解释了在慢性感染中观察到的一系列缺陷。原生动物寄生虫弓形虫感染了世界上三分之一的人口，并在宿主的大脑中引起慢性终身感染。这种感染的后果知之甚少。在这里，我们证明弓形虫感染可以诱导星形胶质细胞生理学的深刻变化，导致神经元网络的显着破坏。病理可以通过上调星形胶质细胞谷氨酸转运蛋白GLT-1，恢复细胞外谷氨酸浓度和EEG功率来挽救。我们认为，这种全球性的神经递质失调时，应考虑确定感染对中枢神经系统的影响。
The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection. The protozoan parasite Toxoplasma gondii infects a third of the world’s population and causes a chronic lifelong infection in the brain of the host. The consequences of such an infection are poorly understood. Here, we demonstrate that Toxoplasma infection can induce profound changes in astrocyte physiology leading to significant disruption of neuronal networks. Pathology can be rescued by upregulating the astrocytic glutamate transporter, GLT-1, restoring concentrations of extracellular glutamate and EEG power. We suggest that such global dysregulation of neurotransmitters should be considered when determining the effects of infection on the CNS.