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System x_c^– and Glutamate Transporter Inhibition Mediates Microglial Toxicity to Oligodendrocytes¹

María Domercq^*, María Victoria Sánchez-Gómez^*, Catherine Sherwin, Estibaliz Etxebarria^*, Robert Fern and Carlos Matute^2,*

^* Departamento de Neurociencias, Universidad del País Vasco, Leioa, Vizcaya, Spain; and Department of Cell Physiology and Pharmacology, University of Leicester, United Kingdom

Elevated levels of extracellular glutamate cause excitotoxic oligodendrocyte cell death and contribute to progressive oligodendrocyte loss and demyelination in white matter disorders such as multiple sclerosis and periventricular leukomalacia. However, the mechanism by which glutamate homeostasis is altered in such conditions remains elusive. We show here that microglial cells, in their activated state, compromise glutamate homeostasis in cultured oligodendrocytes. Both activated and resting microglial cells release glutamate by the cystine-glutamate antiporter system x_c^–. In addition, activated microglial cells act to block glutamate transporters in oligodendrocytes, leading to a net increase in extracellular glutamate and subsequent oligodendrocyte death. The blocking of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or the system x_c^– antiporter prevented the oligodendrocyte injury produced by exposure to LPS-activated microglial cells in mixed glial cultures. In a whole-mount rat optic nerve, LPS exposure produced wide-spread oligodendrocyte injury that was prevented by AMPA/kainate receptor block and greatly reduced by a system x_c^– antiporter block. The cell death was typified by swelling and disruption of mitochondria, a feature that was not found in closely associated axonal mitochondria. Our results reveal a novel mechanism by which reactive microglia can contribute to altering glutamate homeostasis and to the pathogenesis of white matter disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the University of País Vasco, Ministerio de Educación y Ciencia and by Ministerio de Salud y Consumo (to C.M.) and National Institutes of Health Grant NS44875 (to R.F.).

² Address correspondence and reprint requests to Dr. Carlos Matute, Departamento de Neurociencias, Universidad del País Vasco, Leioa, Vizcaya, Spain. E-mail address: carlos.matute{at}ehu.es

³ Abbreviations used in this paper: MS, multiple sclerosis; AAA, aminoadipic acid; AM, acetoxymethyl ester; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; aCSF, artificial cerebrospinal fluid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; EAE, experimental autoimmune encephalitis; JC-1, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline; RON, rat optic nerve; ROS, reactive oxygen species; TBOA, DL-threo--benzyloxyaspartate.

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