Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons.
To evaluate the role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS), we compared the sensitivity of motor neurons and that of dorsal horn neurons to kainic acid (KA). Short exposure to KA resulted in the death of motor neurons, while dorsal horn neurons were unaffected. This selective motor neuron death was completely dependent on extracellular Ca(2+) and insensitive to inhibitors of voltage-operated Ca(2+) or Na(+) channels. It was also completely inhibited by the specific AMPA antagonist LY300164 and by Joro spider toxin (JSTx), a selective blocker of AMPA receptors that lack the edited GluR2 subunit. KA selectively killed those motor neurons that stained positive for the Co(2+) histochemical staining, a measure for the presence of Ca(2+)-permeable AMPA receptors. These results suggest that Ca(2+) entry via Ca(2+)-permeable AMPA receptors is responsible for the selective motor neuron death. As the Ca(2+) permeability of the AMPA receptor is regulated by its GluR2 subunit, we stained motor neurons for GluR2. Immunoreactivity was present in all motor neurons, albeit to a variable degree. However, double-staining experiments demonstrated that motor neurons clearly expressing GluR2, also expressed Ca(2+)-permeable AMPA receptors. This indicates that despite the abundant expression of GluR2, this subunit is excluded from a subset of AMPA receptors and that the activation of these receptors is responsible for the selective motor neuron death.
Van Den Bosch
L
L
Laboratory of Neurobiology, Department of Neurology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Ludo.Vandenbosch@med.kuleuven.ac.be
Vandenberghe
W
W
Klaassen
H
H
Van Houtte
E
E
Robberecht
W
W
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology
D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; C044936:JSTX spider toxin; D009498:Neurotoxins; D018091:Receptors, AMPA; D013111:Spider Venoms; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C085266:talampanel; D009543:Nifedipine; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid