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Cell Rep. 2020 Jan 14;30(2):381-396.e4. doi: 10.1016/j.celrep.2019.12.030.

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

Author information

1
Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: hanson.jesse@gene.com.
2
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
4
Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
5
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
6
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.
7
Department of Pharmaceuticals, Genentech Inc., South San Francisco, CA 94080, USA.
8
Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
9
Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA; Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
10
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jorge.palop@gladstone.ucsf.edu.

Abstract

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.

KEYWORDS:

APP; EEG; J20; MK-801; Nav1.1; SCN1A; epilepsy; interneuron; learning; memory

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