Cell Reports (2020-01-01)

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

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