Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis.
BACKGROUND
Excitotoxic damage is a common pathologic event in a number of neurologic diseases occurring after accumulation of excess extracellular glutamate in the CNS and subsequent overstimulation of glutamate receptors. In gray matter, astrocytes take up synaptically released glutamate and are thus key cells in maintaining glutamate homeostasis. In white matter, oligodendrocytes have been shown to express glutamate transporters, but their role in extracellular glutamate removal is unclear.


OBJECTIVE
To investigate whether cultured human fetal oligodendrocytes functionally express the main glutamate transporters EAAT-1 and EAAT-2.


METHODS
Cultures of fetal human oligodendrocytes were examined by immunocytochemistry and [3H]glutamate uptake, and the findings were correlated with glutamate transporter expression in normal and multiple sclerosis (MS) CNS tissue.


RESULTS
Both EAAT-1 and EAAT-2 were expressed by human oligodendrocytes in vitro. Incubation of oligodendrocytes with the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) reduced EAAT-1 expression and inhibited glutamate uptake by >75%. Furthermore, in normal human white matter, oligodendrocytes were found to be the predominant cells to express EAAT-1 and EAAT-2, both at the mRNA and at the protein level. A small number of astrocytes in white matter expressed these receptors, more so EAAT-1 than EAAT-2. In MS white matter, oligodendrocytes lost expression of EAAT-1 and EAAT-2 receptors in the lesion vicinity.


CONCLUSIONS
Oligodendrocytes appear to be predominant cells for glutamate clearance in human white matter. Glutamate receptor expression and glutamate removal were defective in MS white matter, possibly mediated by TNFalpha, changes that might underlie high extracellular glutamate and an increased risk for glutamate excitotoxicity.
Pitt
David
D
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA. dfpitt@yahoo.com
Nagelmeier
Iris E
IE
Wilson
Heather C
HC
Raine
Cedric S
CS
D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009498:Neurotoxins / Q000378:metabolism / Q000493:pharmacokinetics; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D009498:Neurotoxins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D018698:Glutamic Acid