Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output
Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output
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DOI：
10.1152/jn.00752.2014
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发表时间：
2015-03-15
影响因子：
2.5
通讯作者：
Zhou, Fu-Ming
中科院分区：
文献类型：
--
作者：
Ding, Shengyuan;Li, Li;Zhou, Fu-Ming
帕金森病（Parkinson's disease，PD）时，黑质多巴胺（dopamine，DA）神经元和背侧纹状体DA轴突的缺失较严重，而腹侧被盖区DA神经元和中、腹侧纹状体亚区DA轴突的缺失较轻。严重的DA丢失导致DA受体超敏性，但尚不清楚纹状体黑质轴突终末上DA D1受体（D1Rs）的超敏性是否由严重的纹状体或黑质DA丢失决定。这个问题是重要的，因为这两种可能性影响的程度，纹状体黑质终端与超敏感的D1R，因此强度的直接途径输出。在这里，我们已经调查了这个问题，在转录因子Pitx3突变小鼠有PD样DA损失模式。我们发现，突触前D1R功能上调全球：D1R介导的促进同样增强纹状体黑质GABA输出起源于背侧纹状体的DA损失是严重的和体细胞D1Rs是超敏感的，和纹状体黑质GABA输出起源于中间和腹侧纹状体的DA损失是温和的和体细胞D1Rs不是超敏感的。这些结果表明，严重的黑质DA损失是足以诱导纹状体黑质轴突终末的D1受体的功能上调。因此，在PD中，起源于广泛的纹状体亚区的纹状体黑质轴突终末上的全局增强的D1Rs可能强烈增强D1R刺激后的纹状体黑质GABA输出，可能有助于D1R激动的深刻的运动刺激作用。
In Parkinson's disease (PD), the dopamine (DA) neuron loss in the substantia nigra and the DA axon loss in the dorsal striatum are severe, but DA neurons in the ventral tegmental area and DA axons in middle and ventral striatal subregions are less affected. Severe DA loss leads to DA receptor supersensitivity, but it was not known whether the supersensitivity of the DA D1 receptors (D1Rs) on the striatonigral axon terminal is determined by the severe striatal or nigral DA loss. This question is important because these two possibilities affect the extent of the striatonigral terminals with supersensitive D1Rs and hence the strength of the direct pathway output. Here we have investigated this question in the transcription factor Pitx3 mutant mice that have a PD-like DA loss pattern. We found that the presynaptic D1R function was upregulated globally: the D1R-mediated facilitation was equally enhanced for the striatonigral GABA output originated in the dorsal striatum where the DA loss is severe and the somatic D1Rs are supersensitive, and for the striatonigral GABA output originated in the middle and ventral striatum where the DA loss is moderate and the somatic D1Rs are not supersensitive. These results suggest that severe nigral DA loss is sufficient to induce functional upregulation of the D1Rs on striatonigral axon terminals. Consequently, in PD, the globally enhanced D1Rs on striatonigral axon terminals originated in broad striatal subregions may strongly enhance the striatonigral GABA output upon D1R stimulation, potentially contributing to D1R agonism's profound motor-stimulating effects.