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

Jesse E. Hanson; Keran Ma; Justin Elstrott; Martin Weber; Sandrine Saillet; Abdullah S. Khan; Jeffrey Simms; Benjamin Liu; Thomas A. Kim; Gui-Qiu Yu; Yelin Chen; Tzu-Ming Wang; Zhiyu Jiang; Bianca M. Liederer; Gauri Deshmukh; Hilda Solanoy; Connie Chan; Benjamin D. Sellers; Matthew Volgraf; Jacob B. Schwarz; David H. Hackos; Robby M. Weimer; Morgan Sheng; T. Michael Gill; Kimberly Scearce-Levie; Jorge J. Palop

Cell Reports (Jan 2020)

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

Jesse E. Hanson,
Keran Ma,
Justin Elstrott,
Martin Weber,
Sandrine Saillet,
Abdullah S. Khan,
Jeffrey Simms,
Benjamin Liu,
Thomas A. Kim,
Gui-Qiu Yu,
Yelin Chen,
Tzu-Ming Wang,
Zhiyu Jiang,
Bianca M. Liederer,
Gauri Deshmukh,
Hilda Solanoy,
Connie Chan,
Benjamin D. Sellers,
Matthew Volgraf,
Jacob B. Schwarz,
David H. Hackos,
Robby M. Weimer,
Morgan Sheng,
T. Michael Gill,
Kimberly Scearce-Levie,
Jorge J. Palop

Affiliations

Jesse E. Hanson: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA; Corresponding author
Keran Ma: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Justin Elstrott: Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA
Martin Weber: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Sandrine Saillet: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Abdullah S. Khan: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Jeffrey Simms: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Benjamin Liu: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Thomas A. Kim: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Gui-Qiu Yu: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Yelin Chen: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Tzu-Ming Wang: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Zhiyu Jiang: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Bianca M. Liederer: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA
Gauri Deshmukh: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA
Hilda Solanoy: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Connie Chan: Department of Pharmaceuticals, Genentech Inc., South San Francisco, CA 94080, USA
Benjamin D. Sellers: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA
Matthew Volgraf: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA
Jacob B. Schwarz: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA
David H. Hackos: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Robby M. Weimer: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA; Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA
Morgan Sheng: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
T. Michael Gill: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Kimberly Scearce-Levie: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Jorge J. Palop: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author

Journal volume & issue: Vol. 30, no. 2
pp. 381 – 396.e4

Abstract

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Summary: 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. : 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. Keywords: J20, epilepsy, learning, memory, APP, Nav1.1, SCN1A, interneuron, EEG, MK-801

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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