Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety
Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety
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DOI：
10.1073/pnas.041582598
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发表时间：
2001-02-27
影响因子：
11.1
通讯作者：
Lester, HA
中科院分区：
文献类型：
--
作者：
Labarca, C;Schwarz, J;Lester, HA
产生的敲入小鼠在通道孔门附近的α 4烟碱受体中含有亮氨酸到丝氨酸的突变。这种超敏受体完整表达的小鼠表现出显性的新生儿致命性。这些小鼠在黑质中有严重的多巴胺能神经元缺陷，可能是因为超敏感受体被正常的细胞外胆碱浓度持续激活。在内含子中保留neo选择盒的菌株减少了超敏感受体的表达，并且是活的和可育的。存活的小鼠表现出焦虑增加、运动学习能力下降、过度走动（极低水平的尼古丁消除了这种现象）以及随着年龄的增长，黑质纹状体多巴胺能功能下降。这些敲入小鼠为持续的尼古丁受体激活的病理生理学提供了有用的见解，并可能为帕金森病提供模型。
Knock-in mice were generated that harbored a leucine-to-serine mutation in the alpha4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.