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Glutamate AMPA receptors change in motor neurons of SOD1 G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis‐like disease
Author(s) -
Tortarolo Massimo,
Grignaschi Giuliano,
Calvaresi Novella,
Zennaro Eleonora,
Spaltro Gabriella,
Colovic Milena,
Fracasso Claudia,
Guiso Giovanna,
Elger Bernd,
Schneider Herbert,
Seilheimer Bernd,
Caccia Silvio,
Bendotti Caterina
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20715
Subject(s) - ampa receptor , amyotrophic lateral sclerosis , glutamate receptor , sod1 , excitotoxicity , neuroscience , riluzole , chemistry , long term depression , motor neuron , receptor , nmda receptor , biology , pharmacology , medicine , biochemistry , disease , spinal cord
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder involving the selective degeneration of motor neurons. In a small proportion of patients, ALS is caused by mutations in copper/zinc superoxide dismutase (SOD1), and mice overexpressing SOD1 G93A mutant develop a syndrome that closely resembles the human disease. Excitotoxicity mediated by glutamate AMPA receptors has been suggested to be implicated in the selective susceptibility of motor neurons occurring in ALS. In SOD1 G93A mice, we found that levels of GluR2 AMPA subunit, which plays a pivotal role in the maintenance of calcium impermeability of AMPA receptors, are decreased in spinal motor neurons before symptom onset in concomitance with a modest increase of GluR3 expression, a calcium‐permeable AMPA subunit. This effect can result in a higher number of calcium‐permeable AMPA receptors on motor neurons of SOD1 G93A mice, predisposing these cells to be injured by AMPA‐mediated glutamate firing. In support of this, we showed that treatment with a new noncompetitive AMPA antagonist, ZK 187638, partially protected motor neurons, improved motor function, and prolonged the survival of SOD1 G93A mice. © 2005 Wiley‐Liss, Inc.