NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments.

中文翻译：

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GluN2A NMDA受体增强功能可改善Dravet综合征和阿尔茨海默氏病模型中的大脑振荡，同步性和认知功能。

NMDA受体（NMDAR）在突触功能中发挥亚基特异性作用，并与神经精神病和神经退行性疾病有关。但是，通过变构调节药理学增强NMDAR功能的体内结果和治疗潜力在很大程度上尚不清楚。我们检查了GNE-0723，一种含有GluN2A亚基的NMDAR的正变构调节剂，对Dravet综合征（DS）和阿尔茨海默氏病（AD）小鼠模型的大脑网络和认知功能的体内影响。GNE-0723依赖地增强突触NMDA受体电流，并降低大脑的振荡能力，对低频（12-20 Hz）振荡起主要作用。有趣的是，DS和AD鼠标模型显示出异常的低频振荡功率，该功率与网络超同步紧密相关。GNE-0723治疗可减少DS和AD小鼠模型的异常低频振荡和癫痫样放电，并改善认知功能。含有GluN2A亚基的NMDAR增强剂在具有网络超合和认知障碍的脑部疾病中可能具有治疗优势。