Rescue of long-range circuit dysfunction in Alzheimer's disease models
Rescue of long-range circuit dysfunction in Alzheimer's disease models
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DOI：
10.1038/nn.4137
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发表时间：
2015-11-01
影响因子：
25
通讯作者：
Konnerth, Arthur
中科院分区：
文献类型：
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作者：
Busche, Marc Aurel;Kekus, Maja;Konnerth, Arthur
阿尔茨海默病（AD）与突触连接缺陷有关。这种缺陷可能不限于局部神经元的相互作用，但可能会扩展到长距离的大脑活动，如慢波振荡，这在非快速眼动（非REM）睡眠期间特别突出，并且对于涉及记忆巩固的远端大脑区域的信息整合非常重要。越来越多的证据表明，AD患者的睡眠经常受损，但目前尚不清楚这种损害是否与淀粉样蛋白β（A β）病理学直接相关。在这里，我们证明，慢波活动严重改变，在新皮层，丘脑和海马在小鼠模型的AD淀粉样变性。最值得注意的是，我们的研究结果揭示了慢波传播的A β依赖性损伤，这会导致慢波活动的特征长程相干性的崩溃。通过增强GABA（A）能抑制可以挽救损伤，这一发现确定了A β依赖性大规模回路功能障碍的突触机制。
Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-beta (A beta) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an A beta-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABA(A)ergic inhibition identifies a synaptic mechanism underlying A beta-dependent large-scale circuit dysfunction.