Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer’s disease
Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer’s disease
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DOI：
10.1038/s41386-022-01435-w
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发表时间：
2022-10
影响因子：
7.6
通讯作者：
Shu Shu-Shu;Si-yi Xu;Lei-Ping Ye;Yi Liu;Xiang Cao;Jun-qiu Jia;Hui-jie Bian;Ying Liu;Xiao-Lei Zhu;Yun Xu
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作者：
Shu Shu-Shu;Si-yi Xu;Lei-Ping Ye;Yi Liu;Xiang Cao;Jun-qiu Jia;Hui-jie Bian;Ying Liu;Xiao-Lei Zhu;Yun Xu
阿尔茨海默氏病（AD）是最常见的神经退行性疾病，且起病隐匿。探讨AD早期症状的特点和机制对于AD的早期诊断和干预具有重要作用。在这里，我们发现 APPswe/PS1dE9 小鼠（AD 小鼠）早在 9-11 周龄时就出现了抑郁样行为和短期空间记忆功能障碍。电生理学分析揭示了前额皮质 (PFC) 的兴奋/抑制 (E/I) 失衡。这种 E/I 失衡是由于该区域小白蛋白中间神经元 (PV+IN) 的数量和活性显着减少而引起的。此外，残余PV+IN的光遗传学和化学遗传学激活有效改善了AD小鼠的抑郁样行为并挽救了短期空间记忆。这些结果表明，PFC 在 AD 早期选择性脆弱，前额叶 PV+IN 缺陷在 AD 早期症状的发生和发展中起着关键作用。
Alzheimer’s disease (AD) is the most common neurodegenerative disease and has an insidious onset. Exploring the characteristics and mechanism of the early symptoms of AD plays a critical role in the early diagnosis and intervention of AD. Here we found that depressive-like behavior and short-term spatial memory dysfunction appeared in APPswe/PS1dE9 mice (AD mice) as early as 9-11 weeks of age. Electrophysiological analysis revealed excitatory/inhibitory (E/I) imbalance in the prefrontal cortex (PFC). This E/I imbalance was induced by significant reduction in the number and activity of parvalbumin interneurons (PV+INs) in this region. Furthermore, optogenetic and chemogenetic activation of residual PV+INs effectively ameliorated depressive-like behavior and rescued short-term spatial memory in AD mice. These results suggest the PFC is selectively vulnerable in the early stage of AD and prefrontal PV+INs deficits play a key role in the occurrence and development of early symptoms of AD.