Glutamate receptor expression in multiple sclerosis lesions.
Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca(++)-permeable ionotropic AMPA receptor subunit, was up-regulated on oligodendrocytes in active MS lesion borders, but Ca(++)-impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT-1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5-7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up-regulation.
Newcombe
Jia
J
Department of Neuroinflammation, Institute of Neurology, University College London, London, UK. J.Newcombe@ion.ucl.ac.uk
Uddin
Alim
A
Dove
Rosamund
R
Patel
Bela
B
Turski
Lechoslaw
L
Nishizawa
Yukio
Y
Smith
Terence
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism*
D050580:Excitatory Amino Acid Transporter 3; D018698:Glutamic Acid; D009498:Neurotoxins; D021122:Protein Subunits; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D050496:Vesicular Glutamate Transport Proteins; C493400:SLC1A1 protein, human