VCOM Research Day Program Book 2023

Medical Student Research Biomedical

Caleb Brown BA, VCOM, Seth Boehringer, VT; Patrick Rafael BS, VT; Tullia Johnston BS, MPH, VCOM; Alyssa Ingram BS, VCOM; Nakia Philip BS, VCOM; Pamela VandeVord PhD, VT; Blaise Costa PhD, VCOM Corresponding author: 09 CNS4 Preferentially Potentiates Hypoglutamanergic Disease-Causing Mutant GluN1/2a Subtype of NMDA Receptors

Edward Via College of Osteopathic Medicine-Virginia Campus; Virginia Tech

The normal function of N-methyl D-aspartate (NMDAR) glutamate receptors plays a critical role in cognitive function and pathogenesis of various neuropsychiatric disorders. Children born with mutations in NMDAR subunits, that reduce glutamate potency, suffer from epilepsy, major depression, developmental delay, and intellectual disability. In the current work, to validate the capability of CNS4, - a novel agonist concentration-dependent NMDAR modulator, to preferentially potentiate hypoactive receptors, two disease-causing GluN2A mutants that are known to reduce glutamate potency to 4.4 (A548T) and 126 (V685G) fold were generated, sequenced and assayed using two-electrode voltage

clamp electrophysiology technique. The results obtained from this experiment indicate that CNS4 significantly increased glutamate potency in A548T [(Glu EC50 in µM; 4.68 ±0.7, n=11 vs 1.93 ±0.55, n=5, p<0.05) and V685G (91.67 ±25.35, n=18 vs 0.99 ±0.14, n=17, p<0.01)] mutant expressing 2A receptors when co-expressed with wild type GluN1. However, CNS4 did not alter glutamate potency [(Glu EC50 in µM): 1.89 ±0.11, n=12 vs 2.58 ±0.45, n=5, p>0.05] in the wild-type GluN1/2A receptors. These results reveal that the CNS4 selectively modulates the hypoactive NMDARs. Previous findings demonstrated that CNS4 potentiated NMDA receptor currents disproportionately higher levels

when activated by sub-saturating concentration of glutamate. Therefore, we hypothesize that CNS4 or its analogs will be an appropriate lead candidate for the development of clinically useful compounds to treat drug-resistant neuropsychiatric disorders like anti NMDA receptor encephalitis


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