Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease
Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease
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DOI：
10.1002/(sici)1097-4547(19991115)58:4
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发表时间：
1999-11-15
影响因子：
4.2
通讯作者：
Chesselet, MF
中科院分区：
文献类型：
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作者：
Levine, MS;Klapstein, GJ;Chesselet, MF
我们使用两种亨廷顿病 (HD) 小鼠模型来检查谷氨酸受体敏感性和纹状体电生理学的变化。一种转基因模型由表达人类 HD 基因外显子 1 并携带 141-157 个 CAG 重复序列（R6/2 系）的小鼠组成。第二种模型是 CAG 重复序列“敲入”，由具有不同长度的 CAG 重复序列（CAG71 和 CAG94 重复序列）的小鼠组成。通过使用红外视频显微镜和微分干涉对比光学技术观察脑切片中的神经元来确定体细胞区域的变化（细胞肿胀），从而检查谷氨酸受体激活的影响。与对照组相比，两种模型（R6/2 和 CAG94）中的纹状体和皮质神经元对 N-甲基-D-天冬氨酸（NMDA）的肿胀更快且增加。这种效应是特异性的，因为在暴露于 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）或红藻氨酸（KA）后没有一致的组间差异。细胞内记录显示，R6/2 转基因体中的静息膜电位 (RMP) 比各自对照中的静息膜电位 (RMP) 明显更加去极化。 CAG94 小鼠中的 RMP 也比 CAG71 小鼠或其对照纹状体神经元子集中的 RMP 去极化程度更高。 R6/2 小鼠表现出行为异常和核内含物，证实了之前的结果。然而，CAG71 和 CAG94 敲入却没有，这表明对 NMDA 的敏感性增加可能发生在疾病过程的早期。这些发现意味着 NMDA 拮抗剂或改变 NMDA 受体敏感性的化合物可能可用于治疗 HD，J. Neurosci。资源。 58:515-532, 1999。(C) 1999 Wiley-Liss, Inc.
We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls, This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD, J. Neurosci. Res. 58:515-532, 1999. (C) 1999 Wiley-Liss, Inc.