Late appearance of glutamate transporter defects in a murine model of ALS-parkinsonism dementia complex.
Excitotoxicity has been widely hypothesized to play a major role in various neurodegenerative diseases. We have used a mouse model of ALS-parkinsonism dementia complex (ALS-PDC) of the Western Pacific to explore this hypothesis. Mice fed washed cycad flour, the major epidemiological link to ALS-PDC, showed significant and progressive motor, cognitive, and sensory behavioural deficits [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221]. In addition, glutamate transporter (GLT-1/EAAT2) levels measured by immunohistochemistry with antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B) were significantly down-regulated showing a 'patchy' loss of antibody label centered on blood vessels [Wilson, J.M., Khabazian, I., Pow, D.V., Craig, U.K., Shaw, C.A., 2003. Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model of ALS-PDC. Neuromol. Med. 3 (2), 105-118]. Receptor binding assays showed decreased NMDA and AMPA receptor levels combined with increased GABA(A) receptor levels in various CNS regions. The alterations in GLT-1 variants and the ionotropic receptors are consistent with an increased level of extracellular glutamate. The interaction between environmental toxicity and genetic susceptibility was also tested using mice expressing various Apolipoprotein E (ApoE) genotypes. Mice lacking the ApoE gene showed relative resistance to cycad-induced toxicity as measured by GLT-1B labeling, but all mice expressing the human ApoE isoforms showed a similar loss of GLT-1B. We have further shown that an isolated cycad toxin (beta-sitosterol-beta-d-glucoside, BSSG), previously shown to release glutamate in vitro [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221], can be directly toxic to motor neurons in vivo [Wilson, J.M., Petrik, M.S., Moghadasian, M.H., Shaw, C.A., 2005. Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC. Can. J. Physiol. Pharmacol. 83 (2), 131-141]. However, BSSG-fed mice did not show altered GLT-1B labeling in the spinal cord suggesting that an initial excitotoxic mechanism may not be responsible for the final neuronal loss observed. While glutamate-mediated excitotoxicity is likely involved in the outcomes following cycad/BSSG exposure, the precise location in the cascade of events ultimately leading to neuronal death remains to be determined.
Wilson
J M B
JM
University of British Columbia, Department of Neuroscience, 828 W10th Avenue, Rm 386, Vancouver, BC, Canada V5Z1L8. jmbwilson@gmail.com
Shaw
C A
CA
D027322:Amino Acid Transport System X-AG / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology; D003704:Dementia / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051379:Mice; D016472:Motor Neuron Disease / Q000235:genetics / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000503:physiopathology*
D027322:Amino Acid Transport System X-AG; D001057:Apolipoproteins E