GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models

被引：61

作者：

Hanson, Jesse E. ^{[1
]}

Ma, Keran ^{[6
,7
]}

Elstrott, Justin ^{[2
]}

Weber, Martin ^{[1
]}

Saillet, Sandrine ^{[6
,7
]}

Khan, Abdullah S. ^{[6
]}

Simms, Jeffrey ^{[6
]}

Liu, Benjamin ^{[6
]}

Kim, Thomas A. ^{[6
]}

Yu, Gui-Qiu ^{[6
]}

Chen, Yelin ^{[1
]}

Wang, Tzu-Ming ^{[1
]}

Jiang, Zhiyu ^{[1
]}

Liederer, Bianca M. ^{[3
]}

Deshmukh, Gauri ^{[3
]}

Solanoy, Hilda ^{[1
]}

Chan, Connie ^{[4
]}

Sellers, Benjamin D. ^{[5
]}

Volgraf, Matthew ^{[5
]}

Schwarz, Jacob B. ^{[5
]}

Hackos, David H. ^{[1
]}

Weimer, Robby M. ^{[1
,2
]}

Sheng, Morgan ^{[1
]}

Gill, T. Michael ^{[6
]}

Scearce-Levie, Kimberly ^{[1
]}

Palop, Jorge J. ^{[6
,7
]}

机构：

[1] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Biomed Imaging, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Pharmaceut, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[6] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

来源：

CELL REPORTS | 2020年 / 30卷 / 02期

基金：

美国国家卫生研究院;

关键词：

POSITIVE ALLOSTERIC MODULATORS; MOUSE MODEL; GRIN2A MUTATIONS; SYNAPTIC PLASTICITY; NEURONAL-ACTIVITY; INTERNEURONS; EPILEPSY; MICE; KETAMINE; HYPOFUNCTION;

D O I：

10.1016/j.celrep.2019.12.030

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：381 / +

页数：20

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