Precision Targeting of Heteromeric NMDA Receptors in Age-Related Memory Disorders

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The senior citizen population in the United States is growing, so new therapeutics to treat age-related memory loss are needed to protect personal independence and reduce the burden of Alzheimer’s disease (AD). Ionotropic glutamate receptors of the NMDA subtype (NMDARs) are necessary for normal learning and memory, but NMDAR-targeting therapeutics are minimally effective in lessening the severity of AD symptoms and are not approved to treat memory loss in non-pathological brain aging. NMDARs are biochemically diverse tetramers formed between GluN1 and GluN2 subunits. GluN2A and GluN2B isoforms are abundantly expressed in the hippocampus, but selective ligands that target GluN2A or GluN2B have produced conflicting accounts of NMDAR contribution to memory and neural functions over the lifespan. Unexplored are contributions of tri-heteromeric NMDARs that contain GluN1, GluN2A and GluN2B. This project will innovate the scientific study of NMDARs by developing new ligands that are selective for the GluN1/GluN2A/GluN2B tri-heteromeric NMDAR and investigate how naturally occurring and experimentally induced changes in GluN2 isoforms regulate formation of tri-heteromers in the aging brain. These studies will be significant because they will create new tools to target a broader range of naturally occurring heteromeric NMDARs and identify how interactions between GluN2 isoforms influence neural function in brain aging. Ultimately, these discoveries will open new avenues to develop NMDAR-targeting therapeutics that are effective in preventing or reversing memory loss that emerges in advanced aging.