Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene
Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene
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DOI：
10.1073/pnas.95.11.6480
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Young, AB
中科院分区：
文献类型：
--
作者：
Cha, JHJ;Kosinski, CM;Young, AB
神经递质受体，尤其是谷氨酸和多巴胺受体的缺失是亨廷顿病（HD）患者脑的病理标志之一。表达异常人HD基因外显子1的转基因小鼠（品系R6/2）在9-11周龄时通过未知机制出现神经系统症状。对有症状的12周龄R6/2小鼠的谷氨酸受体（GluR）分析显示，与年龄匹配的同窝对照小鼠相比，1型代谢型GluR（mGluR 1）、mGluR 2、mGluR 3降低，但G蛋白连接的mGluR的mGluR 5亚型未降低，这是通过[（3）H]谷氨酸受体结合、蛋白免疫印迹和原位杂交确定的。离子型α-氨基-3-羟基-5-甲基-4-异恶唑丙酸和红藻氨酸受体也减少，而N-甲基-D-天冬氨酸受体与对照组相比无差异。其他已知在HD中受影响的神经递质受体在R6/2小鼠中也减少，包括多巴胺和毒蕈碱胆碱能受体，但不包括γ-氨基丁酸受体。在8周和12周大的R6/2小鼠的大脑中，D（1）样和D（2）样多巴胺受体的结合率急剧下降到对照组的三分之一。原位杂交表明，早在4周龄时，早在临床症状出现之前，mGluR和D（1）多巴胺受体mRNA就发生了改变。因此，神经递质受体的表达改变先于R6/2小鼠的临床症状，并可能导致随后的病理学。
Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of brains of patients with Huntington disease (HD). Transgenic mice that express exon 1 of an abnormal human HD gene (line R6/2) develop neurologic symptoms at 9-11 weeks of age through an unknown mechanism. Analysis of glutamate receptors (GluRs) in symptomatic 12-week-old R6/2 mice revealed decreases compared with age-matched littermate controls in the type 1 metabotropic GluR (mGluR1), mGluR2, mGluR3, but not the mGluR5 subtype of G protein-linked mGluR, as determined by [(3)H]glutamate receptor binding, protein immunoblotting, and in situ hybridization. Ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors were also decreased, while N-methyl-D-aspartic acid receptors were not different compared with controls. Other neurotransmitter receptors known to be affected in HD were also decreased in R6/2 mice, including dopamine and muscarinic cholinergic, but not gamma-aminobutyric acid receptors. D(1)-like and D(2)-like dopamine receptor binding was drastically reduced to one-third of control in the brains of 8- and 12-week-old R6/2 mice. In situ hybridization indicated that mGluR and D(1) dopamine receptor mRNA were altered as early as 4 weeks of age, long prior to the onset of clinical symptoms. Thus, altered expression of neurotransmitter receptors precedes clinical symptoms in R6/2 mice and may contribute to subsequent pathology.