title: Mechanisms of disease: motoneuron disease aggravated by transgenic expression of a functionally modified AMPA receptor subunit.
abstract: 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.
authors.affiliation: Institute of Pharmacology, University of Heidelberg, Germany.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Groom
authors.forename: Gerald
authors.initials: G
authors.lastname: Müller
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Kornau
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Iris
authors.initials: I
authors.lastname: Bresink
authors.forename: Bettina
authors.initials: B
authors.lastname: Hartmann
authors.forename: Karsten
authors.initials: K
authors.lastname: Tschauner
authors.forename: Stefan
authors.initials: S
authors.lastname: Waibel
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: Lechoslaw
authors.initials: L
authors.lastname: Turski
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001835:Body Weight / Q000502:physiology; D003035:Cobalt / Q000378:metabolism; D004576:Electromyography; D005106:Exploratory Behavior / Q000502:physiology; D005684:Gait / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D016472:Motor Neuron Disease / Q000503:physiopathology*; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D004856:Postural Balance / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics* / Q000502:physiology*; D012018:Reflex / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013534:Survival; D014202:Tremor / Q000235:genetics / Q000503:physiopathology
chemical_list: D018091:Receptors, AMPA; C000606290:SOD1 protein, human; D003035:Cobalt; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1