Prefrontal Cortical GABAergic Dysfunction Contributes to Aberrant UP-State Duration in APP Knockout Mice
Prefrontal Cortical GABAergic Dysfunction Contributes to Aberrant UP-State Duration in APP Knockout Mice
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DOI：
10.1093/cercor/bhw218
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发表时间：
2016-08
期刊：
影响因子：
3.7
通讯作者：
Qingwei Huo;Ming Chen;Quansheng He;Jia-jia Zhang;Bo Li;Kai Jin;Xi Chen;C. Long;Li Yang
中科院分区：
文献类型：
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作者：
Qingwei Huo;Ming Chen;Quansheng He;Jia-jia Zhang;Bo Li;Kai Jin;Xi Chen;C. Long;Li Yang
遗传学和生物化学研究集中在淀粉样β蛋白在阿尔茨海默病发病机制中的作用。相比之下，其前体蛋白，淀粉样前体蛋白（APP），在突触和网络活动的生理作用研究较少。使用APP基因敲除（APP-/-）小鼠模型，我们表明，UP状态的持续时间，这是一个关键特征的皮质突触整合主要发生在慢波睡眠期间，显着增加在前额叶皮层（PFC）在APP的情况下。这是伴随着谷氨酰胺合成酶和组织GABA含量的特定减少和GABABR表达水平的顺序上调。通过应用GABA摄取抑制剂或GABABR激动剂对GABA信号进行药理学强化，挽救了UP状态持续时间的异常，并且前者也改变了GABABR表达。除了揭示APP在PFC网络功能调节中的重要作用外，本研究还证明了GABA信号通路及其受体，特别是GABABRs，作为异常神经网络活动和信息处理的治疗靶点的可行性。
Genetic and biochemical studies have focused on the role of amyloid β protein in the pathogenesis of Alzheimer's disease. In comparison, the physiological roles of its precursor protein, amyloid precursor protein (APP), in synaptic and network activity is less well studied. Using an APP knockout (APP-/-) mouse model, we show that the duration of UP state, which is a key feature of cortical synaptic integration occurring predominantly during slow-wave sleep, is significantly increased in the prefrontal cortex (PFC) in the absence of APP. This was accompanied by a specific reduction in the glutamine synthetase and tissue GABA content and sequential upregulation in the levels of GABABR expression. Pharmacological reinforcement of GABA signaling by application of either a GABA uptake inhibitor or an agonist of GABABR rescued the abnormality of UP-state duration and the former rescues altered GABABR expression as well. In addition to revealing an essential role of APP in the regulation of PFC network function, this study evidences the viability of GABA signaling pathway and its receptors, especially GABABRs, as a target for the treatment of aberrant neural network activity and thus information processing.