PDF(Pubmed)
Abstract：
Glial cell line-derived neurotrophic factor (GDNF) is among the strongest dopamine neuron function- and survival-promoting factors known. Due to this reason, it has clinical relevance in dopamine disorders such as Parkinson\'s disease and schizophrenia. In the striatum, GDNF is exclusively expressed in interneurons, which make up only about 0.6% of striatal cells. Despite clinical significance, histological analysis of striatal GDNF system arborization and relevance to incoming dopamine axons, which bear its receptor RET, has remained enigmatic. This is mainly due to the lack of antibodies able to visualize GDNF- and RET-positive cellular processes; here, we overcome this problem by using knock-in marker alleles. We find that GDNF neurons chemoattract RET+ axons at least seven times farther in distance than medium spiny neurons (MSNs), which make up 95% of striatal neurons. Furthermore, we provide evidence that tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is enriched towards GDNF neurons in the dopamine axons. Finally, we find that GDNF neuron arborizations occupy approximately only twelve times less striatal volume than 135 times more abundant MSNs. Collectively, our results improve our understanding of how endogenous GDNF affects striatal dopamine system function.
摘要：
胶质细胞系衍生的神经营养因子（GDNF）是已知的最强的多巴胺神经元功能和存活促进因子之一。由于这个原因,它在多巴胺疾病如帕金森病和精神分裂症中具有临床相关性。在纹状体，GDNF仅在中间神经元中表达，仅占纹状体细胞的0.6%。尽管有临床意义，纹状体GDNF系统乔化的组织学分析和与进入的多巴胺轴突的相关性，带有它的受体RET，仍然是神秘的。这主要是由于缺乏能够可视化GDNF和RET阳性细胞过程的抗体;在这里，我们通过使用敲入标记等位基因克服了这个问题。我们发现GDNF神经元化学吸引RET+轴突的距离至少比中等多刺神经元（MSN）远7倍，占纹状体神经元的95%。此外，我们提供的证据表明酪氨酸羟化酶，多巴胺合成中的限速酶,向多巴胺轴突中的GDNF神经元富集。最后,我们发现GDNF神经元乔化只占纹状体体积的12倍，而MSNs的135倍。总的来说，我们的研究结果提高了我们对内源性GDNF如何影响纹状体多巴胺系统功能的认识.
