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
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
