Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease.
Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease.
复制标题
DOI：
10.1523/jneurosci.5473-08.2009
复制
发表时间：
2009-02-18
期刊：
影响因子：
--
通讯作者：
Hayden MR
中科院分区：
文献类型：
--
作者：
Graham RK;Pouladi MA;Joshi P;Lu G;Deng Y;Wu NP;Figueroa BE;Metzler M;André VM;Slow EJ;Raymond L;Friedlander R;Levine MS;Leavitt BR;Hayden MR
亨廷顿病(HD)是一种由HD基因中CAG区扩张引起的神经退行性疾病。亨廷顿蛋白(Huntingtin，HTT)的聚谷氨酰胺扩张会导致纹状体中棘神经元以及投射到纹状体的皮质神经元的早期进行性丢失。兴奋性毒性在HD患者纹状体神经元的选择性易损性中起关键作用。在人类HD脑中观察到的早期兴奋性毒性神经病理变化包括喹啉酸(Quin)增加，同时伴有增殖性变化，如棘突密度和树突长度增加。在疾病的后期，退行性类型的改变是明显的，例如树突分枝的丧失，脊柱密度的降低以及3-羟基犬尿氨酸和奎宁水平的降低。目前尚不清楚在疾病的发生和发展过程中，对兴奋性应激的敏感性是否有所不同。在这里，我们通过检测在疾病的不同阶段对兴奋毒性应激的反应来评估YAC128小鼠HD模型中的兴奋毒性表型。我们的结果表明，YAC128小鼠在体外对NMDA(N-甲基-d-天冬氨酸)和体内的Quin表现出更高的敏感性，并出现明显的表型变化。相比之下，10个月大的有症状的YAC128小鼠对Quin诱导的神经毒性具有抵抗力。这些发现与症状前YAC128分离的中等刺神经元(MSN)中NMDAR介导的膜电流显着增加相平行，随着疾病的进展，NMDAR介导的膜电流减少。这些数据突出了突变HTT介导的兴奋性毒性表型的动态性质，并表明HD的治疗方法可能需要改变，具体取决于疾病的阶段和发展。
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.