Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition.
Glutamate uptake is crucial to terminate glutamate signaling and to prevent excitotoxicity. The present study describes the expression of functional glutamate transporters GLAST and GLT-1 in oligodendrocytes by means of electrophysiology, uptake assays, and immunocytochemistry. Inhibition of glutamate uptake, both in oligodendrocyte cultures and in isolated optic nerves, increases glutamate levels and causes oligodendrocyte excitotoxicity, which is prevented by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonists. Furthermore, glutamate transporter inhibitors or antisense oligonucleotides applied onto the optic nerve in vivo lead to oligodendroglial loss, massive demyelination, and severe axonal damage. Overall, these results demonstrate that the integrity of oligodendrocytes and white matter depends on proper glutamate transporter function. Deregulated transporter activity may contribute to acute and chronic white matter damage.
Domercq
María
M
Departamento de Neurociencias, Universidad del País Vasco, Vizcaya, Spain.
Etxebarria
Estibaliz
E
Pérez-Samartín
Alberto
A
Matute
Carlos
C
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009901:Optic Nerve Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014855:Wallerian Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
D027322:Amino Acid Transport System X-AG; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D009498:Neurotoxins; D020319:Oligodeoxyribonucleotides, Antisense; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C493392:Slc1a3 protein, rat