Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model.
Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model.
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与海马过度活跃有关的可逆性 GABA 功能障碍可预测小鼠模型中的早期阿尔茨海默病。
DOI：
10.1186/s13195-021-00859-8
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发表时间：
2021-06-14
期刊：
影响因子：
--
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Li Y;Zhu K;Li N;Wang X;Xiao X;Li L;Li L;He Y;Zhang J;Wo J;Cui Y;Huang H;Zhang J;Wang W;Wang X;Zheng Y
与 β-淀粉样蛋白 (Aβ) 相关的神经元过度活跃被认为是阿尔茨海默病 (AD) 的早期预警信号。尽管越来越多的证据支持这一观点，但其潜在机制仍不清楚。在这里，我们使用来自人类淀粉样前体蛋白（APP）/早老素-1转基因（5XFAD）小鼠及其野生型同窝小鼠的急性海马切片的膜片钳记录了全细胞突触电流和膜电位。本研究采用了生化方法、电子显微镜成像、行为测试以及渗透泵的脑室内药物输送。我们利用 2.5 个月大时的全细胞电生理记录证实了 5XFAD 小鼠海马 CA1 锥体神经元的过度活跃，当时局部 Aβ 阳性斑块尚未形成，仅发生轻度认知功能障碍。我们进一步发现 CA1 锥体神经元的抑制性突触后电流减弱，而兴奋性突触后电流不变，其中内在兴奋性没有变化。此外，转基因小鼠海马突触中 γ-氨基丁酸 A (GABAA) 受体亚基 α1 和 γ2 的密度均降低。有趣的是，在我们的实验条件下，用 GABAA 受体激动剂加波沙朵进行早期干预可逆转 5XFAD 小鼠的海马过度活跃，并适度改善其认知能力。抑制性突触后破坏对 5XFAD 小鼠（甚至可能是 AD）的海马网络和认知异常有重要影响。因此，加强 GABA 能系统可能是早期 AD 的一种有前景的治疗方法。在线版本包含可在 10.1186/s13195-021-00859-8 获取的补充材料。
Neuronal hyperactivity related to β-amyloid (Aβ) is considered an early warning sign of Alzheimer disease (AD). Although increasing evidence supports this opinion, the underlying mechanisms are still unknown. Here, we recorded whole-cell synaptic currents and membrane potentials using patch clamping of acute hippocampal slices from human amyloid precursor protein (APP)/presenilin-1 transgenic (5XFAD) mice and their wild-type littermates. Biochemical methods, electron microscopic imaging, behavioral tests, and intraventricular drug delivery applied with osmotic pumps were used in this study. We confirmed hyperactivity of hippocampal CA1 pyramidal neurons in 5XFAD mice using whole-cell electrophysiological recording at 2.5 months old, when local Aβ-positive plaques had not developed and only mild cognitive dysfunction occurred. We further discovered attenuated inhibitory postsynaptic currents and unchanged excitatory postsynaptic currents in CA1 pyramidal neurons, in which the intrinsic excitability was unchanged. Moreover, the density of both γ-aminobutyric acid A (GABAA) receptor subunits, α1 and γ2, was reduced in synapses of the hippocampus in transgenic mice. Intriguingly, early intervention with the GABAA receptor agonist gaboxadol reversed the hippocampal hyperactivity and modestly ameliorated cognitive performance in 5XFAD mice under our experimental conditions. Inhibitory postsynaptic disruption critically contributes to abnormalities in the hippocampal network and cognition in 5XFAD mice and possibly in AD. Therefore, strengthening the GABAergic system could be a promising therapy for AD in the early stages. The online version contains supplementary material available at 10.1186/s13195-021-00859-8.
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DOI：
10.1196/annals.1379.003
发表时间：
2007-01-01
期刊：
IMAGING AND THE AGING BRAIN
影响因子：
--
作者：
Grutzendler, Jaime;Helmin, Kathryn;Gan, Wen-Biao
通讯作者：
Gan, Wen-Biao
影响因子：
25
作者：
Palop, Jorge J.;Mucke, Lennart
通讯作者：
Mucke, Lennart
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
16.6
作者：
Dinamarca, Margarita C.;Raveh, Adi;Bettler, Bernhard
通讯作者：
Bettler, Bernhard
影响因子：
56.9
作者：
Sando, Richard;Jiang, Xian;Sudhof, Thomas C.
通讯作者：
Sudhof, Thomas C.