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Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model
Jason M B Wilson1, Iraj Khabazian, David V Pow
1Programme in Neuroscience, University of British Columbia, Vancouver, British Columbia.
Neuromolecular Medicine
|May 3, 2003
Summary
Cycad flour consumption in mice reduced glutamate transporter levels, potentially causing excitotoxicity and neurodegeneration similar to ALS-PDC.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Glutamate transporter proteins regulate glutamate levels in the central nervous system (CNS).
- Altered transporter levels are implicated in neurological disorders like ALS and Alzheimer's disease.
- Cycad flour contains a neurotoxin linked to ALS-PDC, a disorder with neurological features.
Purpose of the Study:
- To investigate glutamate transporter (GLT-1/EAAT2) levels in mice exposed to washed cycad flour.
- To determine if cycad exposure induces changes resembling neurodegenerative conditions.
Main Methods:
- Immunohistology using antibodies for GLT-1alpha and GLT-1B splice variants.
- Computer densitometry to quantify transporter levels.
- Western blots to assess protein levels and phosphorylation.
- Receptor-binding assays for NMDA, AMPA, and GABAA receptors.
Main Results:
- Significant down-regulation of GLT-1alpha and GLT-1B in various brain regions and spinal cord of cycad-fed mice.
- A 40% decrease in GLT-1 levels in motor cortex and spinal cord, possibly phosphorylation-dependent.
- Decreased NMDA and AMPA receptor levels, with increased GABAA receptor levels.
- Observed changes suggest increased extracellular glutamate and potential excitotoxicity.
Conclusions:
- Cycad exposure leads to decreased glutamate transporter levels and altered receptor expression in mice.
- These changes indicate early glutamate-mediated excitotoxicity following cycad ingestion.
- Understanding these mechanisms may offer therapeutic targets for early-stage neurodegeneration.