Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis-like disease

Massimo Tortarolo, Giuliano Grignaschi, Novella Calvaresi, Eleonora Zennaro, Gabriella Spaltro, Milena Colovic, Claudia Fracasso, Giovanna Guiso, Bernd Elger, Herbert Schneider, Bernd Seilheimer, Silvio Caccia, Caterina Bendotti

Research output: Contribution to journalArticlepeer-review

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 SOD1G93A 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 SOD1G93A 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 SOD1G93A 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 SOD1G93A mice.

Original languageEnglish
Pages (from-to)134-146
Number of pages13
JournalJournal of Neuroscience Research
Volume83
Issue number1
DOIs
Publication statusPublished - Jan 1 2006

Keywords

  • AMPA antagonist
  • AMPA receptors
  • Amyotrophic lateral sclerosis
  • GluR2
  • SOD1

ASJC Scopus subject areas

  • Neuroscience(all)

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