Himmelberg Marc M, West Ryan J H, Elliott Christopher J H, Wade Alex R
Department of Psychology, The University of York , York , United Kingdom.
Department of Biology, The University of York , York , United Kingdom.
J Neurophysiol. 2018 Mar 1;119(3):957-970. doi: 10.1152/jn.00681.2017. Epub 2017 Nov 15.
The excitotoxic theory of Parkinson's disease (PD) hypothesizes that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD (EOPD) Drosophila models DJ-1α, DJ-1β, and PINK1. We used an electroretinogram to record steady-state visually evoked potentials driven by temporal contrast stimuli. At 1 day of age, all EOPD mutants had a twofold increase in response amplitudes compared with w̄ controls. Furthermore, we found that excitotoxicity occurs in older EOPD models after increased neural activity is triggered by visual stimulation. In an additional analysis, we used a linear discriminant analysis to test whether there were subtle variations in neural gain control that could be used to classify Drosophila into their correct age and genotype. The discriminant analysis was highly accurate, classifying Drosophila into their correct genotypic class at all age groups at 50-70% accuracy (20% chance baseline). Differences in cellular processes link to subtle alterations in neural network operation in young flies, all of which lead to the same pathogenic outcome. Our data are the first to quantify abnormal gain control and excitotoxicity in EOPD Drosophila mutants. We conclude that EOPD mutations may be linked to more sensitive neuronal signaling in prodromal animals that may cause the expression of PD symptomologies later in life. NEW & NOTEWORTHY Steady-state visually evoked potential response amplitudes to multivariate temporal contrast stimuli were recorded in early-onset PD Drosophila models. Our data indicate that abnormal gain control and a subsequent visual loss occur in these PD mutants, supporting a broader excitotoxicity hypothesis in genetic PD. Furthermore, linear discriminant analysis could accurately classify Drosophila into their correct genotype at different ages throughout their lifespan. Our results suggest increased neural signaling in prodromal PD patients.
帕金森病(PD)的兴奋性毒性理论假说认为,多巴胺能神经元的病理生理退化源于疾病早期的神经活动亢进,进而导致线粒体应激和细胞死亡。最近的研究利用果蝇PD模型的视觉系统来探究这一假说。在此,我们研究早发性PD(EOPD)果蝇模型DJ-1α、DJ-1β和PINK1中是否存在异常视觉敏感性和兴奋性毒性。我们使用视网膜电图记录由时间对比度刺激驱动的稳态视觉诱发电位。在1日龄时,与野生型对照相比,所有EOPD突变体的反应幅度增加了两倍。此外,我们发现,在视觉刺激引发神经活动增加后,老年EOPD模型中会出现兴奋性毒性。在另一项分析中,我们使用线性判别分析来测试神经增益控制中是否存在细微变化,这些变化可用于将果蝇正确分类到其年龄和基因型中。判别分析的准确性很高,在所有年龄组中,将果蝇正确分类到其基因型类别的准确率为50-70%(基线为20%的随机概率)。细胞过程的差异与幼蝇神经网络运作的细微改变有关,所有这些都导致相同的致病结果。我们的数据首次量化了EOPD果蝇突变体中的异常增益控制和兴奋性毒性。我们得出结论,EOPD突变可能与前驱动物中更敏感的神经元信号传导有关,这可能导致后期生活中PD症状的表达。新发现和值得注意的是,在早发性PD果蝇模型中记录了对多变量时间对比度刺激的稳态视觉诱发电位反应幅度。我们的数据表明,这些PD突变体中存在异常增益控制和随后的视觉丧失,支持了遗传性PD中更广泛的兴奋性毒性假说。此外,线性判别分析可以在果蝇整个生命周期的不同年龄准确地将其分类到正确的基因型中。我们的结果表明前驱PD患者的神经信号传导增加。