School of Psychology, University of Sussex, Falmer, Brighton, UK.
Genes Brain Behav. 2012 Mar;11(2):137-46. doi: 10.1111/j.1601-183X.2011.00758.x. Epub 2011 Dec 29.
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
与帕金森病（PD）相关的突触前蛋白α-突触核蛋白在多巴胺能神经传递中发挥作用，并与冲动控制障碍（ICD）如药物成瘾有关。在这项研究中，我们通过评估在表达α-突触核蛋白基因的不同小鼠品系中，在 5 选择连续反应时间任务（5-CSRTT）中的运动冲动性差异，来研究α-突触核蛋白与冲动性之间的潜在因果关系。与它们的 C57BL/6J 祖先相比，C57BL/6JOlaHsd 小鼠在染色体缺失方面存在差异，导致两个基因 snca（编码α-突触核蛋白）和 mmrn1（编码多聚蛋白-1）的丢失。当 5-CSRTT 中的预刺激等待间隔增加时，C57BL/6J 小鼠比 C57BL/6JOlaHsd 小鼠表现出更高的冲动性（更多的过早反应）。为了确保降低的冲动性确实与 snca 有关，而不是与相邻基因缺失有关，我们在 5-CSRTT 中测试了野生型（WT）和靶向删除α-突触核蛋白的小鼠（KO）。同样，WT 小鼠比靶向删除α-突触核蛋白的小鼠更冲动。我们正在对 BXD 重组近交系小鼠品系的冲动性进行分析，结果表明冲动性反应与海马体中α-突触核蛋白表达水平之间存在关联。β-和γ-突触核蛋白是突触核蛋白家族的成员，在α-突触核蛋白缺失后可能替代它，在这些小鼠品系中没有发现差异补偿。这些发现表明，α-突触核蛋白可能与冲动性有关，并且可能与一些接受多巴胺能药物治疗的 PD 患者出现的 ICD 有关。
