Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington's disease
Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington's disease
复制标题
DOI：
10.1016/s0006-8993(01)03403-5
复制
发表时间：
2002-03-08
期刊：
影响因子：
2.9
通讯作者：
Fernández-Ruiz, JJ
中科院分区：
文献类型：
--
作者：
Lastres-Becker, I;Berrendero, F;Fernández-Ruiz, JJ
从死后亨廷顿病（HD）大脑基底神经节获得的数据显示，纹状体传出神经元中大麻素CB1受体水平的下降与这些神经元的功能障碍和随后的退化平行。这些发现，以及其他来自线粒体毒素病变引起的HD大鼠模型的发现。提示CB1受体的缺失可能参与了该疾病的发病机制。为了进一步探讨内源性大麻素系统的变化，以及内源性大麻素相关化合物的潜力，我们检测了HD94转基因HD小鼠模型中CB受体的状态。这些小鼠使用tet可调节系统以组织特异性和有条件的方式表达huntingtin外显子1和94个重复的多聚谷氨酰胺束。他们表现出许多HD的特征，如纹状体萎缩、神经元内聚集和进行性肌张力障碍。在这些动物中，我们分析了CB1受体的mRNA水平、特定结合位点的数量和CB1受体激动剂对gtp结合蛋白的激活。与同龄的对照组相比，HD转基因小鼠尾壳核中CB1受体的mRNA转录量显著降低。这种减少与尾壳核及其投射区域（如苍白球、核内核和网状黑质）的受体密度显著降低同时发生。此外，通过激动剂诱导的[S-35]GTPgammaS结合确定，苍白球中CB受体激活的效果降低，并且在黑质中呈下降趋势。在大脑皮层和海马体中没有发现这些变化，尽管这些区域有高水平的突变蛋白表达。CB受体水平的降低伴随着proenkephalin-mRNA水平的降低，但P-mRNA水平不降低。综上所述，这些结果表明CB1受体的缺失可能优先于含有脑啡能CB1受体的纹状体神经元，并进一步暗示CB1受体与随后的HD症状学和神经病理学有关。(C) 2002 Elsevier Science B.V.版权所有
Data obtained from the basal ganglia of postmortem Huntington's disease (HD) brains have revealed that the level of cannabinoid CB1 receptors in striatal efferent neurons decreases in parallel to the dysfunction and subsequent degeneration of these neurons. These findings, and others from rat models of HD generated by lesions with mitochondrial toxins. suggest that the loss of CB1 receptors may be involved in the pathogenesis of the disease. To explore further the changes in the endocannabinoid system, as well as the potential of endocannabinoid-related compounds, we examined the status of CB, receptors in the HD94 transgenic mouse model of HD. These mice express huntingtin exon 1 with a polyglutamine tract of 94 repeats in a tissue-specific and conditional manner using the tet regulatable system. They develop many features of HD, such as striatal atrophy, intraneuronal aggregates and progressive dystonia. In these animals, we analyzed mRNA levels for the CB1 receptor, in addition to the number of specific binding sites and the activation of GTP-binding proteins by CB1 receptor agonists. mRNA transcripts of the CB1 receptor were significantly decreased in the caudate-putamen of HD transgenic mice compared to age-matched littermate controls. The decrease concurred with a marked reduction in receptor density in both the caudate-putamen and its projection areas such as the globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata. Furthermore, the efficacy of CB, receptor activation was reduced in the globus pallidus, as determined by agonist-induced [S-35]GTPgammaS binding, and tended towards a decrease in the substantia nigra. None of these changes was seen in the cerebral cortex and hippocampus, despite high levels of expression of the mutant protein in these regions. The decrease in CB, receptor levels was accompanied by a decrease in the proenkephalin-mRNA levels but not in substance P-mRNA levels. Taken together, these results suggest that the loss of CB1 receptor might be preferential to the enkephalinergic CB1 receptor-containing striatopallidal neurons, and further implicate the CB1 receptor to the subsequent HD symptomatology and neuropathology. (C) 2002 Elsevier Science B.V. All rights reserved.