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

Summary 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, leveraging context-specific dysfunction to devise a surprising treatment. We show that the GluN1 Y647S variant significantly reduces current flow through isolated NMDARs in the mouse brain. However, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors fail to sufficiently engage opposing dendritic ion channels that normally prevent NMDAR overactivation. Boosting negative feedback restores normal dendritic integration and successfully treats seizures in vivo, despite loss-of-function of isolated NMDARs. We demonstrate how seizures arise from loss-of-function NMDARs and target the interaction between a GluN1 variant’s receptor-level effects and its dendritic environment to treat them effectively. Competing Interest Statement As a member of the scientific advisory board of the CureGRIN Foundation, AJR has received financial renumeration. The other authors declare no competing interests. Footnotes This version contains updates to the title, abstract, and main text of the manuscript.