模拟帕金森病的表达人α-synuclein^(A53T)转基因小鼠的早期嗅觉功能观察

Olfactory dysfunction of human α-synuclein^(A53T) transgenic mice in simulation of early symptoms of Parkinson's disease

目的通过对表达人α-synucleinA53T的转基因小鼠嗅觉功能的检测和比较,确立一个可供研究帕金森病早期嗅觉障碍发病机制的模型。方法选取不同月龄的表达人α-synucleinA53T的转基因(TG)小鼠与同窝野生型(WT)对照小鼠;转棒试验评估10月龄TG小鼠随意运动功能是否发生变化;DAB法观察10月龄小鼠脑黑质多巴胺能神经元,进一步验证小鼠是否发生运动功能改变。通过气味鉴别及适应试验,观察小鼠对已熟悉的同种气味的短期记忆能力及适应能力,判断小鼠对陌生气味的辨别能力;通过长间隔记忆试验,检测小鼠对已经暴露过的气味在一定间隔时间后再次暴露的记忆能力;通过隐藏颗粒试验,检测小鼠对食物气味的感知能力,反映嗅觉阈值的水平。结果转棒试验和多巴胺能神经元观察结果均显示10月龄TG小鼠的随意运动功能尚未发生改变。6月龄TG小鼠出现对气味辨别能力的下降,对新旧两种气味的识别时间比较,差异无统计学意义(P=0.120);10月龄TG小鼠表现出更明显的气味识别缺陷(P=0.295)。6月龄TG小鼠寻找到食物的时限长于WT小鼠(P=0.015)。各年龄段小鼠短期记忆及适应能力均正常;但9月龄TG小鼠表现出长期(两次试验间隔时间60、80、100 min)记忆能力减退。结论表达人α-synucleinA53T的转基因小鼠在运动功能改变之前出现嗅觉障碍,表现在气味辨别、记忆、感知能力等方面,能够很好地模拟帕金森病早期嗅觉障碍的表现。

Objective To examine the olfactory function of human oc-synuclein^A53Ttransgenic mice, and establish a model for olfactory dysfunction of early Parkinson＇s disease. Methods Human tx-synuclein^A53T transgenic （TG） mice of different ages and their wildtype （WT） littermates were selected. Rotarod test was used to examine the voluntary motion of TG mice aged 10 months, and DAB method was employed to observe the dopaminergic neurons in substantia nigra in mice aged 10 months for identification of motor function. Odor discrimination and habituation tests were used to observe the short-term memory and habituation of familiar scents and identification of novel scents in mice. Long-term memory test with varied intervals was employed to examine the memory of exposed scents. Besides, buried pellet test was used to investigate the perception on scents of food, which reflected the odor threshold. Results Rotarod test and observation of dopaminergic neurons indicated that the voluntary motion in TG mice aged 10 months did not change. TG mice aged 6 months exhibited subtle deficit in odor discrimination, and there was no significant difference between the time of discrimination of novel scents and that of familiar scents （ P = 0. 120） . TG mice aged 10 months exhibited more significant deficit in discrimination of scents （P=0.295）. The time for finding food in TG mice aged6 months was longer than that in WT mice （P=0.015）. The short memory and habituation of mice of different ages were normal, while TG mice aged 9 mouths exhibited decrease in long-term memory （60 rain, 80 rain and 100 rain of test intervals） . Conclusion Human cx-synucleiuA53T transgenic miceexhibit deficiency in olfaction before motion function alterations, including the aspects of discrimination, memory and perception of scents, which can well simulate the early olfactory disfunction in Parkinson＇s disease.