Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, U.S.A.
ASN Neuro. 2010 Jun 18;2(3):e00036. doi: 10.1042/AN20100007.
Since the identification of the gene responsible for HD (Huntington's disease), many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI (knock-in) mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons) in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.
自鉴定出与亨廷顿病（HD）相关的基因以来，已经产生了许多遗传的小鼠模型。每个模型都采用独特的方法来传递突变基因，并且具有不同的 CAG 重复长度和背景品系。这些模型在遗传背景和表型方面的多样性导致了广泛的争论，即每个模型与人类疾病的相关性。在这里，我们比较和对比了两种 HD 模型（即 YAC128 小鼠和 CAG140 KI 小鼠）的纹状体突触表型，YAC128 小鼠携带全长 huntingtin 基因在酵母人工染色体上，而 CAG140 KI 小鼠携带人类/小鼠嵌合基因，在小鼠基因组背景下表达，同时我们还比较了之前从 R6/2 小鼠获得的发表数据，R6/2 小鼠是突变型 huntingtin 外显子 1 的转基因小鼠。我们表明，YAC128 和 CAG140 KI 小鼠的纹状体中间神经元（medium-sized spiny neurons）具有与 R6/2 小鼠相似的电生理表型。这些表型包括膜输入电阻的逐渐增加、膜电容的减少、纹状体神经元亚群中自发性兴奋性突触后电流的频率降低和自发性抑制性突触后电流的频率增加。因此，尽管这三种 HD 模型之间插入基因的背景存在差异，但在纹状体中间神经元中观察到的主要电生理变化是一致的。这些结果表明这些变化是由于突变型 huntingtin 的表达所致，并且这种改变可以扩展到人类疾病。
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