title: Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity.
abstract: 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.
authors.affiliation: Laboratory of Neurobiology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Elke
authors.initials: E
authors.lastname: Bogaert
authors.forename: Maarten
authors.initials: M
authors.lastname: Dewil
authors.forename: Nicole
authors.initials: N
authors.lastname: Hersmus
authors.forename: Dora
authors.initials: D
authors.lastname: Kiraly
authors.forename: Wendy
authors.initials: W
authors.lastname: Scheveneels
authors.forename: Ilse
authors.initials: I
authors.lastname: Bockx
authors.forename: Dries
authors.initials: D
authors.lastname: Braeken
authors.forename: Nathalie
authors.initials: N
authors.lastname: Verpoorten
authors.forename: Kristien
authors.initials: K
authors.lastname: Verhoeven
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Geert
authors.initials: G
authors.lastname: Callewaert
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
mesh_terms: 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