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Mechanisms of Disease: Motoneuron Disease Aggravated by Transgenic Expression of a Functionally Modified AMPA Receptor Subunit
Author(s) -
KUNER ROHINI,
GROOM ANTHONY J.,
MÜLLER GERALD,
KORNAU HANSCHRISTIAN,
STEFOVSKA VANYA,
BRESINK IRIS,
HARTMANN BETTINA,
TSCHAUNER KARSTEN,
WAIBEL STEFAN,
LUDOLPH ALBERT C.,
IKONOMIDOU CHRYSANTHY,
SEEBURG PETER H.,
TURSKI LECHOSLAW
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2005.tb00034.x
Subject(s) - ampa receptor , amyotrophic lateral sclerosis , sod1 , genetically modified mouse , glutamate receptor , spinal cord , neurodegeneration , transgene , biology , neuroscience , motor neuron , microbiology and biotechnology , receptor , medicine , disease , genetics , gene
A bstract : To reveal whether increased Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.