Rial Daniel, Castro Adalberto A, Machado Nuno, Garção Pedro, Gonçalves Francisco Q, Silva Henrique B, Tomé Angelo R, Köfalvi Attila, Corti Olga, Raisman-Vozari Rita, Cunha Rodrigo A, Prediger Rui D
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, 88049-900, SC, Brazil; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal.
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, 88049-900, SC, Brazil.
PLoS One. 2014 Dec 8;9(12):e114216. doi: 10.1371/journal.pone.0114216. eCollection 2014.
There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/-) to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination), anxiety (elevated plus-maze), depressive-like behavior (forced swimming and tail suspension) and motor function (rotarod, grasping strength and pole). However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP). These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.
有大量证据表明，导致散发性帕金森病（PD）的神经退行性过程在特征性运动症状出现前许多年就已开始。神经精神、感官和认知缺陷被认为是PD的早期非运动表现，并且当前的抗帕金森病治疗并不能减轻这些症状。虽然帕金森基因的功能丧失突变会导致早发性家族性PD，但缺乏Parkin的小鼠并未表现出黑质纹状体通路的自发退化，也未表现出对多巴胺能神经毒素（如6-羟基多巴胺和MPTP）的易感性增强。在此，我们使用外显子3上帕金森基因缺失的成年纯合C57BL/6小鼠（parkin-/-），以进一步研究Parkin在调节非运动特征（即嗅觉、情绪、认知和海马突触可塑性）中的相关性。Parkin-/-小鼠在评估嗅觉（嗅觉辨别）、焦虑（高架十字迷宫）、抑郁样行为（强迫游泳和悬尾）和运动功能（转棒、抓握力和杆试验）的行为测试中表现正常。然而，Parkin-/-小鼠在旷场习惯化、物体定位和改良Y迷宫任务中的表现较差，提示存在程序性和短期空间记忆缺陷。这些行为障碍伴随着海马长时程增强（LTP）受损。这些发现表明，parkin基因的缺失导致海马突触可塑性缺陷，导致记忆缺陷，但无明显的嗅觉、情绪或运动障碍。因此，Parkin-/-小鼠可能是研究PD早期阶段以及测试恢复PD学习和记忆及突触可塑性损伤的新治疗策略的有前景的动物模型。
