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

## TL;DR

A human GluN1 variant in mice causes reduced NMDA receptor function but paradoxically increases seizure risk, which can be treated with magnesium.

## Contribution

Shows how a GluN1 variant causes context-dependent NMDA receptor dysfunction and identifies magnesium as a treatment for seizures.

## Key findings

- GluN1 Y647S variant reduces synaptic NMDAR current in prefrontal neurons.
- Prolonged dendritic excitation in mutant mice leads to seizures despite reduced receptor activity.
- Magnesium supplementation prevents seizures in mice with the GluN1 Y647S variant.

## Abstract

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 in vivo 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.

•GluN1 Y647S+/− variant reduces NMDA receptor function in mouse prefrontal cortex•Despite reduced receptor activity, dendritic excitation is prolonged and triggers seizures•Sensitizing SK channels restores magnesium blockade of NMDA receptors•Oral magnesium threonate prevents seizures in mice with the Y647S+/− variant

GluN1 Y647S+/− variant reduces NMDA receptor function in mouse prefrontal cortex

Despite reduced receptor activity, dendritic excitation is prolonged and triggers seizures

Sensitizing SK channels restores magnesium blockade of NMDA receptors

Oral magnesium threonate prevents seizures in mice with the Y647S+/− variant

Genetics; neuroscience