囊泡单胺转运蛋白2缺陷小鼠多巴胺相关的帕金森病表现的研究

Dopamine related Parkinson disease in transgenic mice with a VMAT2-deficiency

目的观察特定敲除多巴胺能神经元中囊泡单胺转运蛋白2(VMAT2)相关基因的小鼠体内的单胺类神经递质的变化情况,并测定其帕金森病的相关表现.方法取14月龄C57BL/6N背景小鼠(VMAT2^flox/+小鼠)作为对照组,取特定敲除多巴胺能神经元中50%的14月龄VMAT2的小鼠(VMAT2^-/+小鼠)作为实验组,进行一系列行为学测验(各14只雄性小鼠),并利用高效液相色谱电化学法(HPLC-ED)检测两组小鼠(各5~6只)的脑组织中单胺类神经递质的含量,对多巴胺与帕金森病相关表现的关联性进行评价.结果VMAT2缺陷小鼠体内的多巴胺含量明显减低,而其他单胺类神经递质未见明显变化.该组小鼠表现出类似帕金森病的运动功能受损和嗅觉障碍,但是在其他的非运动方面,包括情绪改变、认知功能、睡眠等,均未发现明显功能异常.结论VMAT2与帕金森病密切相关,而多巴胺更多地参与帕金森病的运动性症状以及嗅觉表现中,对于情绪、认知、睡眠等多种非运动症状的贡献不大,此研究为根据临床表现合理选择神经递质相关药物提供了参考.

Objective To evaluate the alterations of the monoamine concentration in the selective vesicular monoamine transporter 2(VMAT2)deficient mice,and observe the symptoms of dopamine related Parkinson disease.Methods The VMAT2^flox/+ mice(14 months)with a background of C57BL/6N were selected as the control group.The VMAT2^-/+ mice(14 months)were developed by the Cre/loxP system to obtain conditional ablation of the Vmat2 gene specifically in the dopaminergic neurons,50%of which were selected as the intervention group.A series of behavioral tests(14 male mice in each group)were carried out,and the monoamine neurotransmitters in the brain tissues of the two groups of mice(5-6 in each group)were detected by high performance liquid chromatography electrochemistry(HPLC-ED).The correlation between dopamine and Parkinson disease was evaluated.Results Mice with selected ablation of the Vmat2 gene in dopaminergic neurons showed selective reduction of dopamine concentration in the brain,and with dysfunctions in motor and olfactory abilities,but no significant deficits of other non-motor functions,such as cognition,emotional performances and sleep patterns.Conclusions VMAT2 is closely related to Parkinson disease,and dopamine is more involved in the motor and olfactory performance of Parkinson disease,but may not be so strong associated with other non-motor symptoms,such as disturbances in emotion,cognition and sleep.This study implies potentially adjustment of therapeutic strategies of Parkinson disease.