Abstract：
Parkinson\'s disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36% ➔ 46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.
摘要：
帕金森病（PD）的特征是错误折叠的α-突触核蛋白（α-syn）蛋白的积累，形成神经内路易体（LB）包裹体。PD的α-syn预制原纤维（PFF）模型概括了α-syn聚集，进行性黑质纹状体变性和运动功能障碍；然而，对PFF诱导的基础和诱发多巴胺（DA）改变的时间过程知之甚少。体内微透析非常适合于在延长的时期内识别神经递质水平的微小变化。在本研究中,成年雄性Fischer344只大鼠接受单侧治疗，纹状体内注射α-synPFFs或磷酸盐缓冲盐水（PBS）。在注射后4或8个月（p.i.），动物进行体内微透析，以评估基础细胞外纹状体DA和代谢物水平，局部KCl诱发的纹状体DA释放和全身性左旋多巴（l-DOPA）的影响。验尸分析表明，在两个时间点，酪氨酸羟化酶（TH）免疫反应性黑质神经元（〜50％）和纹状体TH（〜20％）的PFF诱导的等效减少。与纹状体TH减少相比，纹状体多巴胺转运蛋白（DAT）的减少更为明显，并且在4个月和8个月的p.i.间隔之间进展（36％÷46％）。PFF引起的基底和诱发纹状体DA的显着缺陷，以及电机性能的缺陷，直到8个月p.i.对I-DOPA的反应没有差异，无论PBS或PFF治疗。这些结果表明，基础和诱发纹状体DA在PFF注射后维持数月，两者的丧失与运动功能障碍有关。我们的研究提供了对纹状体中PFF诱导的细胞外多巴胺能缺陷的时间过程和程度的了解。
