Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington's Disease
Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington's Disease
复制标题
DOI：
10.1371/journal.pone.0050717
复制
发表时间：
2012-12-20
期刊：
影响因子：
3.7
通讯作者：
Park, Larry C.
中科院分区：
文献类型：
--
作者：
Heikkinen, Taneli;Lehtimaki, Kimmo;Park, Larry C.
亨廷顿病 (HD) 是一种常染色体神经退行性疾病，其特征是严重的行为、认知和运动缺陷。自从发现导致这种疾病的亨廷顿基因（HTT）突变以来，已经使用不同的 Htt 基因构建体开发了几种小鼠品系。最近，开发了一种新模型，即 zQ175 敲入 (KI) 小鼠（参见 Menalled 等人的描述，[1]），试图将 Htt 基因置于背景中并产生更接近人类 HD 的表型。在这里，我们确认了 Menalled 等人 [1] 报道的行为表型，并将特征扩展到包括脑容量、纹状体代谢物浓度和早期神经生理学变化。两个独立实验室的行为表型的整体可重复性证明了这种新模型的实用性。此外，在 zQ175 小鼠中观察到了让人想起人类 HD 病理学的重要特征：与野生型神经元相比，急性脑切片的电生理记录显示，zQ175 小鼠的中型多棘神经元表现出进行性过度兴奋；纹状体中的谷氨酸传输严重减弱；纯合子小鼠和杂合子小鼠的纹状体和皮质体积分别从3月龄和4月龄开始减少，而纯合子小鼠的全脑体积仅减少。 MR 光谱显示 12 个月大纯合子纹状体中 N-乙酰天冬氨酸浓度降低，谷氨酰胺、牛磺酸和肌酸 + 磷酸肌酸浓度增加，后者也在 12 个月大杂合子中测量到。纯合子的运动、行为和认知缺陷与观察到的结构和代谢变化同时发生。总之，zQ175 KI 模型具有强大的行为、电生理和组织病理学特征，这些特征对于进一步了解 HD 样病理生理学以及评估减缓疾病进展的潜在治疗策略可能很有价值。
Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo-and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.