Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity

Philip Van Damme; Elke Bogaert; Maarten Dewil; Nicole Hersmus; Dora Kiraly; Wendy Scheveneels; Ilse Bockx; Dries Braeken; Nathalie Verpoorten; Kristien Verhoeven; Vincent Timmerman; Paul Herijgers; Geert Callewaert; Peter Carmeliet; Ludo Van Den Bosch; Wim Robberecht

doi:10.1073/pnas.0705046104

Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity

Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14825-30. doi: 10.1073/pnas.0705046104. Epub 2007 Sep 5.

Authors

Philip Van Damme¹, Elke Bogaert, Maarten Dewil, Nicole Hersmus, Dora Kiraly, Wendy Scheveneels, Ilse Bockx, Dries Braeken, Nathalie Verpoorten, Kristien Verhoeven, Vincent Timmerman, Paul Herijgers, Geert Callewaert, Peter Carmeliet, Ludo Van Den Bosch, Wim Robberecht

Affiliation

¹ Laboratory of Neurobiology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium.

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / metabolism
Animals
Astrocytes / enzymology
Astrocytes / physiology*
Calcium / metabolism
Cells, Cultured
Coculture Techniques
Excitatory Amino Acid Agonists / pharmacology
Female
Gene Expression / physiology
Genes, Reporter
Luciferases / metabolism
Models, Biological
Motor Neurons / drug effects*
Motor Neurons / metabolism*
Motor Neurons / physiology
Mutation
Patch-Clamp Techniques
Proteins / metabolism
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Rats, Wistar
Receptors, AMPA / genetics*
Receptors, AMPA / metabolism*
Spinal Cord / cytology
Superoxide Dismutase / genetics
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

Excitatory Amino Acid Agonists
Proteins
RNA, Messenger
Receptors, AMPA
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Luciferases
Superoxide Dismutase
glutamate receptor ionotropic, AMPA 2
Calcium