Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer's Disease.
Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer's Disease.
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DOI：
10.1523/eneuro.0426-17.2018
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发表时间：
2018-03
期刊：
影响因子：
3.4
通讯作者：
Oren I
中科院分区：
文献类型：
--
作者：
Brown R;Lam AD;Gonzalez-Sulser A;Ying A;Jones M;Chou RC;Tzioras M;Jordan CY;Jedrasiak-Cape I;Hemonnot AL;Abou Jaoude M;Cole AJ;Cash SS;Saito T;Saido T;Ribchester RR;Hashemi K;Oren I
网络高兴奋性是阿尔茨海默病（AD）以及许多AD转基因小鼠模型的一个特征。虽然阿尔茨海默病患者的高兴奋性和阿尔茨海默病动物模型具有某些共同特征，但机制上的重叠仍有待确定。我们的目的是确定AD模型中网络高兴奋性的特征，这些特征可能与AD患者的癫痫样活动特征有关。我们研究了引起家族性AD的淀粉样前体蛋白（APP）突变小鼠的网络高兴奋性，并比较了过表达人类APP的转基因模型（hAPP） （J20）和生理水平表达APP的敲入模型（APPNL/F）。我们记录了小鼠的连续长期皮质电图（ECoG）活动，并研究了昼夜周期、行为和大脑状态对其的调节作用。我们报告说，虽然j20表现出频繁的间隔尖峰（IISs），但APPNL/F小鼠没有。在J20小鼠中，IISs在白天最为普遍，昼夜节律调节与睡眠有关。对大脑状态的进一步分析表明，j20的IIS与快速眼动睡眠（REM）的特征有关。我们没有发现任何证据表明胆碱能变化可能有助于j20的IIS-circadian耦合。与j20相比，在AD患者中捕获IIS的颅内记录显示，IIS在非快速眼动（NREM）睡眠中频繁发生。APP过表达小鼠和AD患者IIS睡眠阶段耦合的显著差异表明，小鼠和人类的网络高兴奋性可能存在不同的机制。我们假设IIS的睡眠阶段耦合应该是识别最接近概括人类AD的网络高兴奋性的小鼠AD模型的重要考虑因素。
Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.