| Abstract No.: | 305 |
| Country: | Canada |
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| Title: | ALTERED NMDA RECEPTOR TRAFFICKING AND SIGNALING IN MOUSE MODELS OF HUNTINGTON DISEASE |
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| Authors/Affiliations: | 1 Lynn Raymond*;
1 University of British Columbia, Department of Psychiatry, Vancouver, BC, Canada
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| Content: | Huntington disease (HD) is an autosomal dominantly inherited, progressive disorder of movement, mood and cognition. Degeneration of striatal GABAergic medium-sized spiny neurons (MSNs) occurs early in the disease, which is caused by expansion >35 of a CAG repeat in the HD gene, encoding the protein huntingtin (Htt) with a polyglutamine expansion near the N-terminus. Early studies in human HD autopsy brain tissue, and in animal models striatally-injected with glutamate receptor agonists, have suggested a role for N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity in this selective neurodegeneration. Consistent with those results, studies in transgenic and knock-in mouse models of HD demonstrate early up-regulation of NMDAR current and toxicity in striatal MSNs. In particular, we have reported a polyQ length-dependent mutant Htt enhancement of NMDAR toxicity in MSN cultures from newborn YAC transgenic mice. Enhanced toxicity correlates with increased NMDAR current and peak calcium response when comparing YAC18 (non-pathogenic, control), YAC46 and YAC72 mice, and increased NMDA-evoked current results from augmented forward trafficking of NMDARs to the neuronal surface in YAC72 MSNs. In contrast, in the most severe HD model – YAC128 – cultured MSNs show NMDAR current and peak calcium responses similar to those of MSNs from control (wild-type, YAC18) mice, while NMDAR toxicity remains enhanced because of increased sensitivity to calcium induction of the mitochondrial permeability transition. Here we report that tonic calpain activity is significantly increased in the striatum of YAC128 compared with wild-type mice, resulting in augmented calpain-mediated cleavage of the NR2B subunit of NMDARs and accelerated removal of receptors from the surface of cultured MSNs. The rate of loss of surface NMDARs in YAC128 MSNs is reduced to wild-type levels, and the steady-state surface to internal ratio of NMDARs is significantly increased, by treatment with a calpain inhibitor. Despite the tonic down-regulation of NMDAR surface expression by enhanced calpain activity in YAC128 MSNs, treatment with a calpain inhibitor significantly protects MSNs from NMDA-induced apoptosis. Increased understanding of the complex regulation of NMDAR activity and cell death signaling in HD striatal MSNs will facilitate development of targeted therapies for this devastating disease. |
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