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首页> 美国卫生研究院文献>The Journal of Neuroscience >Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions
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Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions

机译：韦弗基因在含多巴胺的神经系统中的表达是剂量依赖性的并且会影响纹状体和非纹状体区域

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In an earlier report we presented evidence pointing to a differential effect of the mutant gene weaver on the dopamine-containing fiber systems innervating the striatum. In mice homozygous for the weaver mutation, there is a severe loss of dopamine in the caudoputamen, the main target of the nigrostriatal system. By contrast, dopamine is entirely conserved in the nucleus accumbens, a target of the mesolimbic system, and is moderately affected in the olfactory tubercle. The present study shows that these defects in dopamine are gene dose- dependent, that they are established by the end of the first month of life, and that the losses are permanent and not progressive. As in homozygous weavers, the greatest defects in striatal dopamine in heterozygous weavers occur in the dorsolateral caudoputamen and the lateral olfactory tubercle. The abnormalities in the striatal dopamine content of weaver mice are not accompanied by abnormalities in the turnover of dopamine, judging from measurements of the dopamine metabolite dihydroxyphenylacetic acid. Norepinephrine content is also normal in each striatal region. No deficits in striatal dopamine occur in mice homozygous for the mutant genes staggerer and Purkinje cell degeneration, which, like the weaver mutation, result in ataxia and cerebellar pathology. A survey of nonstriatal regions in the weaver mice showed that the effects of the weaver gene on the dopamine- containing innervation of the forebrain are not confined to striatal targets but also extend to the septum and the hypothalamus. By contrast, dopamine in the frontal cortex, the amygdala, the olfactory bulb, and the retina is entirely spared. The pattern and extent of loss of dopamine in the weaver forebrain is thus region- and system- specific. In confirmation of our initial findings, a ca. 30% depletion of dopamine occurs in the weaver midbrain, the region containing the cell bodies of origin of the mesostriatal dopamine systems. A comparison of histofluorescent sections through weaver and control midbrains revealed a reduction of catecholamine-containing neurons in the pars compacta of the weaver animals. These results point to a subpopulation of dopamine-containing neurons as primary targets of the weaver gene or as being closely associated with such primary targets. As a gene-dose effect has also been shown for the cerebellar granule cell loss in the weaver, the mutant gene must have at least 2 cellular targets. We suggest that the cerebellar and mesostriatal pathologies may be linked by a common molecular mechanism.
机译：在较早的报告中，我们提供了证据表明突变基因编织者对支配纹状体的含多巴胺的纤维系统具有不同的作用。在纯合织法突变的小鼠中，caudoputamen（黑质纹状体系统的主要靶点）中的多巴胺大量流失。相比之下，多巴胺在伏隔核（中脑边缘系统的靶标）中完全保守，在嗅结节中受到中度影响。本研究表明，多巴胺中的这些缺陷是基因剂量依赖性的，它们在生命的第一个月结束时就已经确定，并且损失是永久性的而不是逐步的。如在纯合织布工中，杂合织布工中纹状体多巴胺的最大缺陷发生在背外侧caudoputamen和外侧嗅结节中。从对多巴胺代谢产物二羟基苯基乙酸的测量结果来看，织布小鼠的纹状体多巴胺含量异常并不伴有多巴胺周转异常。每个纹状体区域的去甲肾上腺素含量也正常。在纯合子小鼠中，纹状体多巴胺和浦肯野细胞变性的纯合子中没有出现纹状体多巴胺的缺陷，这与韦弗突变一样，导致共济失调和小脑病理。一项对编织者非纹状体区域的调查显示，编织者基因对前脑含多巴胺的神经支配的影响不仅限于纹状体靶点，而且还延伸至隔膜和下丘脑。相比之下，额叶皮层，杏仁核，嗅球和视网膜中的多巴胺完全被省掉了。因此，织布前脑中多巴胺损失的方式和程度是区域和系统特定的。为了证实我们的初步发现，多巴胺的消耗减少了30％发生在韦弗中脑，该区域包含中肋多巴胺系统起源的细胞体。通过织布工和对照中脑的组织荧光切片的比较显示，在织布工动物的腮腺中含儿茶酚胺的神经元减少。这些结果表明，含有多巴胺的神经元亚群是织造基因的主要靶标，或者与这类主要靶标紧密相关。由于在织布工中小脑颗粒细胞丢失也显示出基因剂量效应，因此突变基因必须具有至少2个细胞靶标。我们建议小脑和中胚层的病理可能是由共同的分子机制联系在一起的。

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