氯硝西泮改善APP/PS1痴呆模型小鼠大脑超兴奋性和认知障碍

Clonazepam attenuates brain hyerexcitability and cognitive deficits of APP/PS1 mice

目的探讨APP/PS1痴呆模型小鼠大脑中间神经元的数量变化和大脑超兴奋性以及认知功能3者之间的关系。方法利用7个月龄雄性小鼠WT小鼠和APP/PS1小鼠,通过免疫荧光染色,观察海马齿状回区神经肽Y(NPY)和皮质NPY、小清蛋白(PV)、钙网膜蛋白(CR)阳性中间神经元数量变化。将7个月龄雄性APP/PS1分为2组,注射生理盐水组和注射氯硝西泮(CLZ)组,CLZ按0.025mg·kg-1的剂量在每次实验前30min进行腹腔注射,通过新物体识别实验记录和分析小鼠探索新物体的时间和速度之后进行脑电图(EEG)监测,记录和分析每小时癫痫样高尖波的数量变化。结果 APP/PS1小鼠和野生型相比,海马NPY阳性中间神经元和皮质的NPY、PV、CR阳性中间神经元的数量都大量减少,注射CLZ组APP/PS1小鼠较APP/PS1小鼠海马和皮质癫痫样高尖波的数量都显著减少,注射CLZ的APP/PS1小鼠较APP/PS1小鼠探索新物体时间有增加趋势。结论 APP/PS1小鼠的中间神经元数量减少导致大脑超兴奋性和认知障碍,CLZ能改善APP/PS1小鼠大脑超兴奋性和认知障碍。

Objective To investigate the relationship among the number of brain neurons, brain hyper- excitability and cognitive function of APP/PS1 mice. Method The number of neuropeptide （ NPY ） positive interneurons in hippocampal DG and NPY, parvalbumin （ PV ）, ealretinin （ CR ） positive interneurons in cortex of 7-month-old APP/PS1 transgenic mice and their wildtype littermates was quantified by immunofluorescence staining. 7-month-old APP/PS1 mice was injected intraperitoneally at 0.025 mg kg-1 half an hour prior to analysis. The frequency of epilepsy-like spikes was analyzed by electroencephalogram （ EEG ） The cognition was examined by novel object recognition test. Results The number of NPY positive interneurons in hippocampal DG and NPY, PV, CR positive interneurons in cortex of 7-month-old APP/PS1 transgenic mice was significantly decreased compared with that in wild-type mice. APP/PS1 mice injected with clonazepam （ CLZ ） showed less cortical epilepsy-like spikes and an increasing trend of recognition index compared to control APP/PS1 mice which were injected with saline. Conclusion The decrease in the number of interneurons in APP/PS1 mice resulted in brain hyper-excitability and cognitive impairment, and CLZ improved the brain excitability and cognitive impairment in APP/PS1 mice.