Cremer J N, Amunts K, Graw J, Piel M, Rösch F, Zilles K
Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, D-52425 Jülich, Germany; Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital, RWTH Aachen University, and JARA - Translational Brain Medicine, D-52062 Aachen, Germany.
Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, D-52425 Jülich, Germany; Cécile & Oskar Vogt Institute of Brain Research, Heinrich-Heine University Düsseldorf, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.
Neuroscience. 2015 Jan 29;285:11-23. doi: 10.1016/j.neuroscience.2014.10.050. Epub 2014 Nov 5.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic α1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology.
帕金森病（PD）是第二常见的神经退行性疾病，其特征是黑质纹状体多巴胺能神经传递改变。与关于多巴胺系统受损的大量数据相比，关于主要非多巴胺能神经递质系统在帕金森病中的作用的证据相对有限。因此，我们全面研究了纯合无晶状体小鼠大脑中谷氨酸、γ-氨基丁酸（GABA）、乙酰胆碱、肾上腺素、5-羟色胺、多巴胺和腺苷的神经递质受体的密度和分布，这些小鼠因影响Pitx3基因的突变而具有特征性表现。这种遗传模型在神经病理学、症状学和药理学水平上表现出帕金森病的关键特征。为了从系统层面了解受体变化，我们使用定量受体放射自显影技术对11个脑区的19个不同受体结合位点进行了表征。我们分别证明了许多受体类型和脑区的神经递质受体密度存在显著的差异变化。最显著的是，在不同脑区发现GABA受体和相关苯二氮䓬结合位点强烈上调，同时纹状体烟碱型乙酰胆碱和5-羟色胺能受体密度下调。此外，谷氨酸能海人藻酸、毒蕈碱型乙酰胆碱、肾上腺素能α1和多巴胺能D2/D3受体的密度也有不同程度的改变。这些结果为Pitx3(ak)小鼠神经递质受体的表达提供了新的见解，支持了对帕金森病患者病理研究的结果，并指出了可能的潜在机制。数据表明Pitx3(ak)小鼠是研究神经递质受体在帕金森病中作用的合适新模型。我们的研究强调了非多巴胺能系统在帕金森病中的相关性以及对其分子病理学理解的重要性。
