Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease
Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease
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DOI：
10.1098/rstb.1999.0449
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发表时间：
1999-06-29
影响因子：
6.3
通讯作者：
Young, AB
中科院分区：
文献类型：
--
作者：
Cha, JHJ;Frey, AS;Young, AB
神经递质受体的改变是亨廷顿氏病（HD）神经变性的病理标志。然而，这些改变的意义还不确定，可能仅仅反映了脑细胞的损失。在人类HD患者中，神经递质受体的改变是否发生在症状出现之前尚不确定。最近，我们开发了转基因小鼠，其中包含人类HD基因的一部分，并发展出进行性异常神经表型。在HD中改变的神经递质受体（谷氨酸、多巴胺、乙酰胆碱和腺苷受体）在转基因小鼠的大脑中减少，在某些情况下，在行为或运动症状出现之前。在转基因小鼠中，神经递质受体的改变发生在神经元死亡之前。此外，受体的改变在某些受体中是选择性的，即n -甲基- d -天冬氨酸和γ -氨基丁酸受体！是不变的。最后，受体的减少发生在相应mRNA种类的选择性减少之前，这表明特定基因的转录发生了改变。这些结果表明：(i)受体减少先于临床症状的发展，因此可能有助于临床症状的发展；（ii）特定基因转录的改变可能是HD的关键病理机制。
Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain of transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N-methyl-D-aspartate and gamma-aminobutyric acid receptors! are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.