title: GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis.
abstract: AMPA receptor-mediated excitotoxicity has been implicated in the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Motor neurons in vitro are particularly vulnerable to excessive AMPA receptor stimulation and one of the factors underlying this selective vulnerability is the presence of a large proportion of Ca2+ -permeable (i.e. GluR2-lacking) AMPA receptors. However, the precise role of GluR2-lacking AMPA receptors in motor neuron degeneration remains to be defined. We therefore studied the impact of GluR2 deficiency on motor neuron death in vitro and in vivo. Cultured motor neurons from GluR2-deficient embryos displayed an increased Ca2+ influx through AMPA receptors and an increased vulnerability to AMPA receptor-mediated excitotoxicity. We deleted the GluR2 gene in mutant SOD1G93A mice by crossbreeding them with GluR2 knockout mice. GluR2 deficiency clearly accelerated the motor neuron degeneration and shortened the life span of mutant SOD1G93A mice. These findings indicate that GluR2 plays a pivotal role in the vulnerability of motor neurons in vitro and in vivo, and that therapies that limit Ca2+ entry through AMPA receptors might be beneficial in ALS patients.
authors.affiliation: Laboratory of Neurobiology, K. U. Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Dries
authors.initials: D
authors.lastname: Braeken
authors.forename: Geert
authors.initials: G
authors.lastname: Callewaert
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D018091:Receptors, AMPA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C104722:glutamate receptor ionotropic, AMPA 2