Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated.
APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice.
Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.
方法:本研究以4月龄的APPswe/PS1dE9小鼠(APP小鼠)作为AD早期的动物模型。用戊四氮建立急性/慢性化学点燃癫痫模型。进行脑电图和Racine评分以评估癫痫发作。行为测试用于评估认知和情绪。电生理学,进行蛋白质印迹和免疫荧光以检测突触的改变,GABA能系统组分和NRG1-ErbB4信号传导。此外,将NRG1脑室内给药至APP小鼠,然后评估其抗癫痫和认知作用。
结果:APP小鼠对癫痫的易感性增加,并导致海马突触损伤和认知障碍。电生理分析显示海马中GABA能传递减少。这种异常的GABA能传递涉及小白蛋白中间神经元(PVIns)数量的减少以及GABA合成和转运水平的降低。我们还发现了由PV+Ins损失介导的NRG1-ErbB4信号传导受损。NRG1给药可有效减少4月龄APP小鼠的癫痫发作和改善认知功能。
结论:我们的结果表明,异常的GABA能传递介导了海马过度兴奋,进一步的激发/抑制失衡,并促进AD早期癫痫的发生。适当的NRG1给药可以下调癫痫发作易感性并挽救认知功能。我们的研究为干预AD和癫痫的合并症提供了潜在的方向。