Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons
Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons
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DOI：
10.1016/j.expneurol.2015.09.002
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发表时间：
2015-11-01
影响因子：
5.3
通讯作者：
Svenningsson, P.
中科院分区：
文献类型：
--
作者：
Caudal, D.;Alvarsson, A.;Svenningsson, P.
帕金森病（PD）是一种神经退行性疾病，其特征在于黑质多巴胺能神经元的进行性损失和存在含有称为路易体的α-突触核蛋白的聚集体。病毒载体诱导的多巴胺能神经元中α-突触核蛋白的过表达代表了比常用的神经毒素模型更好地再现疾病进展的PD模型。以前使用这种模型的研究报告了运动和认知障碍，而抑郁症，情绪和焦虑表型的描述较少。为了研究这些精神病表型，Sprague-Dawley大鼠接受双侧注射表达人α-突触核蛋白或GFP的重组腺相关病毒（AAV）载体到黑质丘脑部。在两个时间点评估行为：注射后3周和8周。我们报告，黑质α-突触核蛋白过度表达导致黑质多巴胺能细胞的损失伴随着一个较小的细胞损失在腹侧被盖区，并减少纹状体多巴胺能纤维的密度。AAV-a-synudein组在载体施用后8周表现出适度但显著的运动损伤。AAV-α-突触核蛋白组在3周后的强迫游泳测试中显示出抑郁样行为，并且在第8周降低了蔗糖偏好。在这两个时间点，α-突触核蛋白的过度表达与皮质酮的过度活跃的下丘脑-垂体-肾上腺（HPA）轴调节有关。抑郁样表型也与黑质脑源性神经营养因子和spinophilin水平下降，并与纹状体水平的活性调节细胞因子相关蛋白。这项研究表明，腺相关病毒介导的多巴胺神经元中的α-突触核蛋白过表达不仅可用于建模帕金森病的运动障碍，还可用于建模抑郁症。这项研究还提供了证据表明，抑郁症的实验性帕金森病是相关的HPA轴失调和突触可塑性蛋白质的改变。(C)2015 Elsevier Inc. All rights reserved.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing alpha-synuclein called Lewy bodies. Viral vector-induced overexpression of alpha-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague-Dawley rats received bilateral injections of a recombinant adeno-associated virus (AAV) vector expressing human alpha-synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8 weeks post-injection. We report that nigral alpha-synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-alpha-synudein group exhibited modest, but significant motor impairments 8 weeks after vector administration. The AAV-alpha-synuclein group displayed depressive-like behavior in the forced swim test after 3 weeks, and reduced sucrose preference at week 8. At both timepoints, overexpression of alpha-synuclein was linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone. The depressive-like phenotype was also correlated with decreased nigral brain-derived neurotrophic factor and spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated protein. This study demonstrates that AAV-mediated alpha-synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in experimental Parkinsonism is correlated to dysregulation of the HPA axis and to alterations in proteins involved in synaptic plasticity. (C) 2015 Elsevier Inc. All rights reserved.