Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease
Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease
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DOI：
10.1016/j.neuron.2007.07.025
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发表时间：
2007-09-06
期刊：
影响因子：
16.2
通讯作者：
Mucke, Lennart
中科院分区：
文献类型：
--
作者：
Palop, Jorge J.;Chin, Jeannie;Mucke, Lennart
神经网络功能障碍可能在阿尔茨海默病（AD）中起重要作用。在人类淀粉样前体蛋白（hAPP）转基因小鼠中，易受AD影响的神经元回路也受到影响。大脑中具有高水平淀粉样β肽的hAPP小鼠出现AD样异常，包括认知缺陷和齿状回中钙相关蛋白的消耗，齿状回是一个关键参与学习和记忆的区域。在这里，我们报告说，hAPP小鼠在皮层和海马网络，这是与GABA能发芽，增强突触抑制，和突触可塑性缺陷在齿状回的自发性非惊厥性癫痫发作活动。许多抗体诱导的神经元的变化可以模拟在非转基因小鼠兴奋毒素的挑战，并阻止在hAPP小鼠通过阻断过度兴奋。海马中网络兴奋性和代偿性抑制机制的异常增加可能导致hAPP小鼠中A β诱导的神经功能缺损，也可能导致AD患者中的神经功能缺损。
Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Ab-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to A beta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.