Gerstenberger Julia, Bauer Anne, Helmschrodt Christin, Richter Angelika, Richter Franziska
Institute of Pharmacology, Pharmacy and Toxicology, Department of Veterinary Medicine, Leipzig University, An den Tierkliniken 15, 04103 Leipzig, Germany.
Behav Brain Res. 2016 May 1;304:102-10. doi: 10.1016/j.bbr.2016.02.017. Epub 2016 Feb 12.
Development of disease modifying therapeutics for Parkinson's disease (PD), the second most common neurodegenerative disorder, relies on availability of animal models which recapitulate the disease hallmarks. Only few transgenic mouse models, which mimic overexpression of alpha-synuclein, show dopamine loss, behavioral impairments and protein aggregation. Mice overexpressing human wildtype alpha-synuclein under the Thy-1 promotor (Thy1-aSyn) replicate these features. However, female mice do not exhibit a phenotype. This was attributed to a potentially lower transgene expression located on the X chromosome. Here we support that female mice overexpress human wildtype alpha-synuclein only about 1.5 fold in the substantia nigra, compared to about 3 fold in male mice. Since female Thy1-aSyn mice were shown previously to exhibit differences in corticostriatal communication and synaptic plasticity similar to their male counterparts we hypothesized that female mice use compensatory mechanisms and strategies to not show overt motor deficits despite an underlying endophenotype. In order to unmask these deficits we translated recent findings in PD patients that sensory abnormalities can enhance motor dysfunction into a novel behavioral test, the adaptive rotating beam test. We found that under changing sensory input female Thy1-aSyn mice showed an overt phenotype. Our data supports that the integration of sensorimotor information is likely a major contributor to symptoms of movement disorders and that even low levels of overexpression of human wildtype alpha-synuclein has the potential to disrupt processing of these information. The here described adaptive rotating beam test represents a sensitive behavioral test to detect moderate sensorimotor alterations in mouse models.
帕金森病（PD）是第二常见的神经退行性疾病，其疾病修饰疗法的开发依赖于能够重现疾病特征的动物模型。只有少数模拟α-突触核蛋白过表达的转基因小鼠模型表现出多巴胺丧失、行为障碍和蛋白质聚集。在Thy-1启动子（Thy1-aSyn）控制下过表达人类野生型α-突触核蛋白的小鼠复制了这些特征。然而，雌性小鼠并未表现出该表型。这被归因于位于X染色体上的转基因表达可能较低。在此，我们证实，与雄性小鼠约3倍的表达水平相比，雌性小鼠在黑质中人类野生型α-突触核蛋白的过表达仅约为1.5倍。由于先前已表明雌性Thy1-aSyn小鼠在皮质纹状体通信和突触可塑性方面表现出与其雄性对应物相似的差异，我们推测雌性小鼠使用补偿机制和策略，尽管存在潜在的内表型，但仍不表现出明显的运动缺陷。为了揭示这些缺陷，我们将帕金森病患者的最新研究结果转化为一种新的行为测试——适应性旋转光束测试，该研究结果表明感觉异常可增强运动功能障碍。我们发现，在不断变化的感觉输入下，雌性Thy1-aSyn小鼠表现出明显的表型。我们的数据支持，感觉运动信息的整合可能是导致运动障碍症状的主要因素，即使是低水平的人类野生型α-突触核蛋白过表达也有可能破坏这些信息的处理。本文所述的适应性旋转光束测试是一种灵敏的行为测试，可用于检测小鼠模型中的中度感觉运动改变。
