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aInstitute of Pharmacology, University of Heidelberg, D-69120 Heidelberg, Germany bEisai London Research Laboratories, University College London, London WC1E 6BT, United Kingdom cHönower Strasse 152, D-12623 Berlin, Germany dCenter for Molecular Neurobiology (ZMNH), University of Hamburg, D-20251 Hamburg, Germany eDepartment of Pediatric Neurology, Children's Hospital, Technical University, D-01307 Dresden, Germany fResearch and Development, Asche AG, D-22763 Hamburg, Germany gDepartment of Neurology, University of Ulm, D-89081 Ulm, Germany hDepartment of Molecular Neurobiology, Max-Planck-Institute for Medical Research, D-69120 Heidelberg, Germany iSolvay Pharmaceuticals Research Laboratories, 1381 CP Weesp, the Netherlands
Address for correspondence: Prof. Dr. med. L. Turski, Solvay Pharmaceuticals Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, the Netherlands. Voice: +31-294-479498; fax: +31-294-477109. les.turski{at}solvay.com
To reveal whether increased Ca2+ permeability of glutamate AMPA channels triggered by the transgene for GluR-B(N) induces decline in motor functions and neurodegeneration in the spinal cord, we evaluated growth, motor coordination, and spinal reflexes in transgenic GluR-B(N) and wild-type (wt) mice. To reveal whether the transgenic GluR-B(N) expression aggravates the course of motoneuron disease in SOD1 mice, we mated heterozygous GluR-B(N) and SOD1 [C57BL6Ico-TgN(hSOD1-G93A)1Gur] mice to generate double-transgenic progeny. The phenotypic sequelae in mice carrying mutations were evaluated by monitoring growth, motor coordination, and survival. Neuronal degeneration was assessed by morphological and stereological analysis of spinal cord and brain. We found that transgenic expression in mice of GluR-B(N)-containing glutamate AMPA receptors with increased Ca2+ permeability leads to a late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progressed over the entire life span, but manifested clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerated disease progression, aggravated severity of motor decline, and decreased survival. These observations reveal that moderate, but persistently elevated Ca2+ influx via glutamate AMPA channels causes degeneration of spinal motoneurons and motor decline over the span of life. These features resemble the course of sporadic amyotrophic lateral sclerosis (ALS) in humans and suggest that modified function of glutamate AMPA channels may be causally linked to pathogenesis of ALS.
Key Words: amyotrophic lateral sclerosis • AMPA channels • GluR-B subunits • glutamate • spinal reflexes • neurodegeneration
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