AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
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DOI：
10.1073/pnas.0507313103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Huerta, PT
中科院分区：
文献类型：
--
作者：
Chang, EH;Savage, MJ;Huerta, PT
人们普遍认为，阿尔茨海默氏病（AD）始于突触功能障碍，最终导致认知障碍和痴呆。稳态突触缩放是一种在AD发病时可能至关重要的机制，但尚未进行实验研究。在这个过程中，神经元的突触强度被修改，从而维持细胞的整体兴奋性。在这里，我们调查是否突触缩放介导的L-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）有助于病理在双敲入（2 × KI）小鼠携带人类突变的淀粉样前体蛋白和早老素-1的基因。通过使用全细胞记录，我们发现，2 × KI小鼠表现出年龄相关的AMPAR介导的诱发电流和自发，微型电流的缩小。电子显微镜分析进一步证实了突触AMPAR减少。此外，2 x KI小鼠在双向可塑性（长时程增强和长时程抑制）和记忆灵活性方面表现出年龄相关的缺陷。这些结果表明，AMPAR是AD的重要突触靶点，并提供证据表明，认知障碍可能涉及突触后AMPAR功能的下调。
It is widely thought that Alzheimer's disease (AD) begins as a malfunction of synapses, eventually leading to cognitive impairment and dementia. Homeostatic synaptic scaling is a mechanism that could be crucial at the onset of AD but has not been examined experimentally. In this process, the synaptic strength of a neuron is modified so that the overall excitability of the cell is maintained. Here, we investigate whether synaptic scaling mediated by L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) contributes to pathology in double knockin (2 x KI) mice carrying human mutations in the genes for amyloid precursor protein and presenilin-1. By using whole-cell recordings, we show that 2 x KI mice exhibit age-related downscaling of AMPAR-mediated evoked currents and spontaneous, miniature currents. Electron microscopic analysis further corroborates the synaptic AMPAR decrease. Additionally, 2 x KI mice show age-related deficits in bidirectional plasticity (long-term potentiation and long-term depression) and memory flexibility. These results suggest that AMPARs are important synaptic targets for AD and provide evidence that cognitive impairment may involve downscaling of postsynaptic AMPAR function.