Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity.
Influx of Ca(2+) ions through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca(2+) permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca(2+) ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.
Van Damme
Philip
P
Laboratory of Neurobiology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium.
Bogaert
Elke
E
Dewil
Maarten
M
Hersmus
Nicole
N
Kiraly
Dora
D
Scheveneels
Wendy
W
Bockx
Ilse
I
Braeken
Dries
D
Verpoorten
Nathalie
N
Verhoeven
Kristien
K
Timmerman
Vincent
V
Herijgers
Paul
P
Callewaert
Geert
G
Carmeliet
Peter
P
Van Den Bosch
Ludo
L
Robberecht
Wim
W
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D018408:Patch-Clamp Techniques; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology