NMDAR enhancer with benefits for Alzheimer´s disease

NMDA receptors play subunit-specific roles in synaptic function with connections to neuropsychiatric and neurodegenerative disorders. In the study GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models, published in Cell Reports, Researchers from Genentech, Gladstone Institute of Neurological Disease and University of California investigate the effect of GNE-0723 on NMDARs. GNE-0723 is a positive allosteric modulator of NDMDARs containing the subunit GluN2A. The researchers are specifically interested in its effect on cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer’s disease (AD). In this work, Dynaflow Resoleve was used to investigate the effect of GNA-0723 on NMDAR activation in order to investigate its pharmacological potential.

Using Dynaflow Resolve, the researchers expose cells expressing GluN2A-containing NMDARs to varying concentrations of glutamate in the presence and absence of GNE-0723. Whole cell patch clamp recordings made at increasing concentration of glutamate revealed that GNE-0723 both enhances the peak current and slows current deactivation. The enhancement of the NMDAR current in the presence of GNE-0723 was reflected in a significant lowering of the EC₅₀ compared to the control experiment without GNE-0723.

These results, together with results from experiments in mouse models for AD and DS, reveal GNE-0723 as a useful compound for pharmacological enhancement of GluN2A-containing NMDARs. The results suggests that GluN2A PAMs can normalize hyperactive brain networks and can enhance memory retention.

We are very happy to see that Hanson et al. have chosen to use Dynaflow Resolve in their work. We are excited to see where their research will take them in the future.