Context matters: Integrative NMDA receptor dysfunction reveals effective seizure treatment in mice with a human patient GluN1 variant

Intractable epilepsy and cognitive deficits arise from missense variants in GRIN genes encoding subunits of the N-Methyl-D-Aspartate receptor (NMDAR). Here, we go beyond typical assessments of isolated receptors to explore the impact of a human GluN1 variant across multiple scales of native NMDAR signaling. We show that isolated and integrated NMDAR signaling are differentially affected in brain slices of transgenic mice with the heterozygous GluN1 Y647S patient variant. Loss-of-function NMDARs paradoxically prolong NMDAR-dependent dendritic integration, extending cortical network activity and increasing vulnerability for seizure-like events. We identify that loss-of-function NMDARs fail to engage canonical negative feedback via calcium-activated potassium channels. To prevent hyperexcitability from NMDAR overdrive, we test an unorthodox treatment to increase NMDAR Mg ²⁺ block. Oral treatment with magnesium-L-threonate significantly reduces seizure occurrence and severity in GluN1 Y647S patient variant mice. This work demonstrates that higher-order functional context is useful in predicting effective treatment for seizures arising from NMDAR disruption.