title: Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease.
abstract: Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG tract in the HD gene. Polyglutamine expansion of huntingtin (htt) results in early, progressive loss of medium spiny striatal neurons, as well as cortical neurons that project to the striatum. Excitotoxicity has been postulated to play a key role in the selective vulnerability of striatal neurons in HD. Early excitotoxic neuropathological changes observed in human HD brain include increased quinolinate (QUIN) concurrent with proliferative changes such as increased spine density and dendritic length. In later stages of the disease, degenerative-type changes are apparent, such as loss of dendritic arborization, a reduction in spine density and reduced levels of 3-hydroxykynurenine and QUIN. It is currently unknown whether sensitivity to excitotoxic stress varies between initiation and progression of disease. Here, we have assessed the excitotoxic phenotype in the YAC128 mouse model of HD by examining the response to excitotoxic stress at different stages of disease. Our results demonstrate that YAC128 mice display enhanced sensitivity to NMDA ex vivo and QUIN in vivo before obvious phenotypic changes. In contrast, 10-month-old symptomatic YAC128 mice are resistant to QUIN-induced neurotoxicity. These findings are paralleled by a significant increase in NMDAR-mediated membrane currents in presymptomatic YAC128 dissociated medium spiny neurons progressing to reduced NMDAR-mediated membrane currents with disease progression. These data highlight the dynamic nature of the mutant htt-mediated excitotoxic phenotype and suggests that therapeutic approaches to HD may need to be altered, depending on the stage and development of the disease.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Prasad
authors.initials: P
authors.lastname: Joshi
authors.forename: Ge
authors.initials: G
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Wu
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Figueroa
authors.forename: Martina
authors.initials: M
authors.lastname: Metzler
authors.forename: Véronique M
authors.initials: VM
authors.lastname: André
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Slow
authors.forename: Lynn
authors.initials: L
authors.lastname: Raymond
authors.forename: Robert
authors.initials: R
authors.lastname: Friedlander
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism / Q000633:toxicity; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D009924:Organ Culture Techniques; D010641:Phenotype; D017378:Quinolinic Acid / Q000378:metabolism / Q000633:toxicity; D013312:Stress, Physiological / Q000235:genetics*; D013570:Synaptic Membranes / Q000378:metabolism / Q000473:pathology; D055366:Synaptic Potentials / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D009498:Neurotoxins; D016202:N-Methylaspartate; D017378:Quinolinic Acid