Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant

Mutations in N-methyl-D-aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, revealing unexpected context-dependent phenotypes. We show that the GluN1 Y647S variant significantly reduces current flow through pharmacologically isolated synaptic NMDARs in prefrontal neurons. Yet in intact local circuits, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors appear deficient in engaging opposing dendritic ion channels that normally curtail NMDAR-dependent excitation. Boosting SK channel activity normalizes dendritic integration, whereas slight decreases in extracellular magnesium further extend abnormally prolonged integration in mutant mice. We find that magnesium supplementation successfully treats seizures <i>in vivo</i> in the transgenic mice, despite loss-of-function of NMDARs. Overall, we disentangle a GluN1 variant's receptor-level effects and its dendritic impact to treat seizures effectively.