Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation
Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation
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DOI：
10.1111/j.1471-4159.2005.03169.x
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发表时间：
2005-08-01
影响因子：
4.7
通讯作者：
von Hörsten, S
中科院分区：
文献类型：
--
作者：
Bauer, A;Zilles, K;von Hörsten, S
亨廷顿氏病（HD）是一种常染色体显性遗传的进行性神经退行性疾病，由编码亨廷顿蛋白的基因CAG/聚谷氨酰胺重复扩增引起。我们最近建立了一种转基因HID大鼠模型，它显示出一种缓慢进展的表型，类似于人类成年发病类型的疾病。在本研究中，我们采用定量多示踪放射自显像和高分辨率正电子发射断层扫描技术系统地评估了2岁大鼠大脑中17种传递受体的分布和密度。杂合动物M-2乙酰胆碱（对照组增加148 +/- 16%，p > 0.001, n = 7）、尼古丁（对照组增加149 +/- 16%，p > 0.01, n = 6）和α(2)去甲肾上腺素能受体（对照组增加141 +/- 15%，p > 0.001, n = 6）的密度分别升高。这些受体的密度在纯合子动物中降低。M、乙酰胆碱、5-HT2A 5-羟色胺、A（2A）腺苷、D-1和D-2多巴胺和GABA(A)受体密度在异合子和纯合子动物中均有所降低。其他被调查的受体系统显示出很小的变化或不受影响。目前的数据表明，CAG/聚谷氨酰胺重复扩增在亨廷顿病大鼠模型中适度增加，其特征是神经受体密度的亚型选择性和区域特异性变化。特别是，有证据表明突触前定位的胆碱能和去甲肾上腺素能受体在对亨廷顿病病理的反应中起着重要作用。
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HID, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M-2 acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M, acetylcholine, 5-HT2A serotonin, A(2A) adenosine, D-1 and D-2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynapticaily localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.