Glutamate uptake is decreased tardively in the spinal cord of FALS mice

Canton, Thierry; Pratt, Jeremy; Stutzmann, Jean‐Marie; Impérato, Assunta; Boireau, A.

doi:10.1097/00001756-199803300-00001

Cited by 63 publications

(40 citation statements)

References 8 publications

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“…We also evaluated rotarod performance during the same time period and found that the performance rate was reduced from ~71 days of age, although it was not consistently significantly different until 113 days of age (due in part to the use of non-parametric tests and our conservative definition of a consistent significant difference). Our findings are in agreement with those of Canton et al (1998; and Weydt et al (2003), which also demonstrated the presence of chronic limb muscle weakness. Interestingly, we found that SOD1-G93A and control mice exhibited similar levels of locomotor activity, even at end-stage, despite early deficits in grip strength and rotarod performance.…”

Section: Fore-and Hindlimb Motor Deficitssupporting

confidence: 92%

“…In contrast, other studies revealed long-standing deficits apparent at earlier time-points. Using a grip strength meter, Canton et al (1998) demonstrated reduced combined limb grip strength in SOD1-G93A mice compared to controls from approximately 35 days of age. Another study by Canton et al (2001) demonstrated significantly reduced combined limb grip strength in SOD1-G93A mice compared to controls from 55 days of age.…”

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 98%

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Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

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Section: Fore-and Hindlimb Motor Deficitssupporting

confidence: 92%

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 98%

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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“…In mutant SOD1 mice, several studies have shown decreased EAAT2 protein and downregulation of glutamate-transport activity in affected CNS areas (9,15,20,23,41,151,153,155). Similar results are found in the SOD1-G93A and H46R transgenic rats (41, 68) (see also Fig.…”

Section: Astroglia Dysfunction In Als Occurs Through Different Synergsupporting

confidence: 74%

“…Several studies in the mouse model of ALS showed that changes in the EAAT2 expression levels and glutamateuptake activity are found only in the ventral horn of the affected spinal cord at a late stage of disease (9,23,41). An .…”

Section: Astroglia Dysfunction In Als Occurs Through Different Synergmentioning

confidence: 99%

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Foran

Trotti²

2009

Antioxidants & Redox Signaling

247

141

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Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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“…This may weaken the tolerance of motoneurons to glutamate. Second, mutant SOD1 is also capable of impairing the function of glial glutamate transporter GLT-1 (Canton et al 1998;Pedersen et al 1998;Trotti et al 1999). Particularly striking is the recent finding that transgenic rats expressing mutant SOD1 G93A have a dramatic decrease in GLT-1 in the ventral horn of their spinal cords (Howland et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Jung

Higgins

2002

Journal of Neurochemistry

183

111

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.

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Glutamate uptake is decreased tardively in the spinal cord of FALS mice

Cited by 63 publications

References 8 publications

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

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