摘要
唐氏综合症(DS)的认知障碍是由数百个基因的异常表达引起的。然而,位于21号染色体“唐氏综合症关键区域”中间的基因KCNJ6的影响似乎很突出。KCNJ6编码G蛋白门控内整流钾通道的GIRK2 (KIR3.2)亚基,其作为GABAB, m2, 5HT1A, A1和许多其他突触后代谢受体的效应器。GIRK2亚基在新皮层、小脑和海马体中大量表达。通过控制静息膜电位和神经元兴奋性,GIRK2通道可能因此影响大脑中对学习和记忆重要区域的神经回路的突触可塑性和稳定性。在这里,我们讨论了关于KCNJ6/GIRK2在DS和阿尔茨海默病(AD)模型中神经元异常和认知障碍中的作用的最新实验数据。结果令人信服地表明,在唐氏综合征小鼠遗传模型中,通过GIRK2通道的信号通路异常增强,并且通过药物或遗传手段部分抑制GIRK2通道可以恢复突触可塑性,改善受损的认知功能。另一方面,在AD模型(如早期淀粉样病模型)中,通过GIRK2通道的信号传导下调。在这些模型中,减少GIRK2通道信号可促进神经元过度活动,引起兴奋-抑制失衡和神经元死亡。因此,通过GIRK通道激活剂或GABAB受体激动剂激活GABAB/GIRK2信号可能减少a β诱导的多动和随后的神经元死亡,从而在AD模型中发挥神经保护作用。
关键词: 唐氏综合症,阿尔茨海默病,GIRK2通道,遗传疾病,神经元多动,KCNJ6。
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