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

Abstract

Highlights d AD and DS mice display aberrant 12-to 20-Hz oscillations associated with epileptic spikes d GluN2A-NMDAR enhancement reduces aberrant oscillations and spikes in AD and DS mice d Chronic GluN2A-NMDAR activation improves cognitive functions in AD and DS mice d GluN2A PAMs could benefit brain disorders with hypersynchrony and cognitive deficits

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

“…The impact of GluN2A subunit in AD has been recently taken into account also as a potential pharmacological target. In particular, GNE-0723, a novel positive allosteric modulator of GluN2A-containing NMDAR, was shown to ameliorate the cognitive deficits in a mouse model of AD (J20) [195], supporting the importance of the involvement of synaptic NMDAR neurotransmission in AD pathogenesis.…”

“…However, more recent literature identified both increased [189][190][191] and decreased LTP responses, probably depending on experimental conditions and how efficiently the seizure-induced LTP-like condition was realized [192][193][194]. Finally, in a recent work Hanson et al found that the seizure phenotype was ameliorated by the use of a Positive Allosteric Modulator of GluN2A in a mouse model of Dravet syndrome [195]. In this case, the activation of GluN2A-containing NMDAR was able to improve the brain oscillations and neuronal hypersynchrony, improving the epileptic discharges.…”

Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

“…Recently, a positive allosteric modulator called GNE-0723 that can boost the activity of NMDAR containing GluN2A subunit contained in both excitatory pyramidal neurons and inhibitory interneurons has been tested in hAPP-J20 mice (Hanson et al, 2020 ). This compound was found to decrease aberrant low-frequency oscillations (12–20 Hz), network hypersynchrony, and memory deficits in hAPP-J20 mice, suggesting that this drug is able to reinstate the excitation/inhibition balance.…”

“…Moreover, intraperitoneal injection of the benzodiazepine clonazepam, which increase GABAergic function by acting on GABA A receptors, has been shown to rescue slow waves and sleep-dependent memory consolidation in APP23×PS45 mice (Busche et al, 2015b). Recently, a positive allosteric modulator called GNE-0723 that can boost the activity of NMDAR containing GluN2A subunit contained in both excitatory pyramidal neurons and inhibitory interneurons has been tested in hAPP-J20 mice (Hanson et al, 2020). This compound was found to decrease aberrant low-frequency oscillations (12-20 Hz), network hypersynchrony, and memory deficits in hAPP-J20 mice, suggesting that this drug is able to reinstate the excitation/inhibition balance.…”

Phenotypic Differences between the Alzheimer’s Disease-Related hAPP-J20 Model and HeterozygousZbtb20Knock-Out Mice

“…Heterozygous hAPP transgenic mice from line J20 (hAPP-J20 mice) are widely used to study the roles of hAPP and its metabolites in AD-related alterations of neural functions ( Palop et al, 2003 ; Saganich et al, 2006 ; Ongali et al, 2010 ; Pozueta et al, 2013 ; Wright et al, 2013 ; Palop and Mucke, 2016 ; Flores et al, 2018 ; Ameen-Ali et al, 2019 ; Etter et al, 2019 ; Ferreira et al, 2020 ; Hanson et al, 2020 ; Johnson et al, 2020 ; Royea et al, 2020 ; Shabir et al, 2020 ). In this model, the platelet-derived growth factor (PDGF) β chain promoter directs neuronal expression of an alternatively spliced minigene encoding isoforms hAPP695, hAPP751, and hAPP770 each carrying mutations (“Swedish” and “Indiana”) that cause autosomal dominant familial AD (FAD) in humans ( Rockenstein et al, 1995 ; Mucke et al, 2000 ).…”