Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model of ALS-PDC.
Glutamate transporter proteins appear crucial to controlling levels of glutamate in the central nervous system (CNS). Abnormal and/or decreased levels of various transporters have been observed in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) and in other neurological disorders. We have assessed glutamate transporter (GLT-1/EAAT2) levels in mice fed washed cycad flour containing a suspected neurotoxin that induces features resembling the Guamanian disorder, ALS-PDC. Down-regulation of glutamate transporter subtypes was detected by immunohistology using antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B). Immunohistology showed a "patchy" loss of antibody label with the patches centered on blood vessels. Computer densitometry showed significantly decreased GLT-1alpha levels in the spinal cord and primary somatosensory cortex of cycad-fed mice. GLT-1B levels were significantly decreased in the spinal cord, in the motor, somatosensory, and piriform cortices, and in the striatum. Western blots showed a 40% decrease in frontal motor cortex and lumbar spinal cord of cycad-fed mice that appeared to be phosphorylation-dependent. Receptor-binding assays showed decreased NMDA and AMPA receptor levels and increased GABAA receptor levels in cycad-fed mice cortex. These receptor data are consistent with an increased level of extracellular glutamate. The generalized decrease in GLT-1, decreased excitatory amino acid receptor levels, and increased GABAA receptor levels may reflect an early glutamate-mediated excitotoxicity following cycad exposure. Deciphering the series of events leading to neurodegeneration in cycad-fed animals may provide clues leading to therapeutic approaches to halt the early stages of disease progression.
Programme in Neuroscience, University of British Columbia, Vancouver, British Columbia.
Jason M B
JM
Wilson
Iraj
I
Khabazian
David V
DV
Pow
Ulla K
UK
Craig
Christopher A
CA
Shaw
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D010936:Plant Extracts / Q000633:toxicity; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D027342:Excitatory Amino Acid Transporter 2; D009498:Neurotoxins; D010936:Plant Extracts; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D018698:Glutamic Acid