Differential susceptibility to excitotoxic stress in YAC128 mouse models of HD between initiation and progression of disease
| Autor: | Graham, Rona K., Pouladi, Mahmoud A., Joshi, Prasad, Lu, Ge, Deng, Yu, Wu, Nan-Ping, Figueroa, Bryan E., Metzler, Martina, André, Véronique M., Slow, Elizabeth J., Raymond, Lynn, Friedlander, Robert, Levine, Michael S., Leavitt, Blair R., Hayden, Michael R. |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
N-Methylaspartate
Dendritic Spines Neurotoxins Synaptic Membranes Brain Mice Transgenic Quinolinic Acid Synaptic Potentials Synaptic Transmission Article Brain Ischemia Disease Models Animal Mice Huntington Disease Organ Culture Techniques Phenotype nervous system Stress Physiological Nerve Degeneration Disease Progression Animals Genetic Predisposition to Disease Cells Cultured |
| Popis: | 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 (N-methyl-d-aspartate) ex vivo and QUIN in vivo prior to obvious phenotypic changes. By contrast, 10 months-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 (MSNs) 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. |
| Databáze: | OpenAIRE |
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