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

• Published in: Cell reports (Cambridge) Vol. 30; no. 2; pp. 381 - 396.e4
• Main Authors: Hanson, Jesse E., Ma, Keran, Elstrott, Justin, Weber, Martin, Saillet, Sandrine, Khan, Abdullah S., Simms, Jeffrey, Liu, Benjamin, Kim, Thomas A., Yu, Gui-Qiu, Chen, Yelin, Wang, Tzu-Ming, Jiang, Zhiyu, Liederer, Bianca M., Deshmukh, Gauri, Solanoy, Hilda, Chan, Connie, Sellers, Benjamin D., Volgraf, Matthew, Schwarz, Jacob B., Hackos, David H., Weimer, Robby M., Sheng, Morgan, Gill, T. Michael, Scearce-Levie, Kimberly, Palop, Jorge J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2020; Elsevier
• Subjects: Allosteric Regulation - drug effects; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; APP; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; CHO Cells; Cognition - drug effects; Cricetulus; Cyclopropanes - pharmacology; Disease Models, Animal; EEG; Epilepsies, Myoclonic - drug therapy; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - metabolism; epilepsy; Humans; interneuron; J20; learning; Male; memory; Mice; Mice, Inbred C57BL; MK-801; Nav1.1; Nitriles - pharmacology; Pyrazoles - pharmacology; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - metabolism; SCN1A; Thiazoles - pharmacology; epilepsy; APP; MK-801; memory; Nav1.1; EEG; J20; interneuron; learning; SCN1A
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.12.030

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. [Display omitted] •AD and DS mice display aberrant 12- to 20-Hz oscillations associated with epileptic spikes•GluN2A-NMDAR enhancement reduces aberrant oscillations and spikes in AD and DS mice•Chronic GluN2A-NMDAR activation improves cognitive functions in AD and DS mice•GluN2A PAMs could benefit brain disorders with hypersynchrony and cognitive deficits Hanson et al. examine the therapeutic effects of enhancing GluN2A-subunit-containing NMDAR function in Dravet syndrome and Alzheimer’s disease mice. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in both disease models. GluN2A NMDAR enhancers may benefit brain disorders with network hypersynchrony and cognitive impairments.