# Negr1 deficiency alters glutamate signalling and kynurenine pathway in a mouse model of psychiatric disorders

## TL;DR

This study shows that NEGR1 deficiency in mice affects glutamate signaling and kynurenine pathway metabolism, with effects varying by sex and brain region.

## Contribution

The study reveals sex-dependent modulation of NMDA receptor function and kynurenine pathway by NEGR1 deficiency in a mouse model.

## Key findings

- Negr1-deficient males showed altered behavioral responses to NMDA receptor antagonism compared to wild-type controls.
- Gene expression of NMDA receptor subunits varied by sex and brain region in Negr1-deficient mice.
- Kynurenine pathway metabolites exhibited genotype- and sex-dependent changes in Negr1-deficient mice.

## Abstract

The NEGR1 gene has been implicated in several psychiatric disorders, and increased NMDA receptor binding density has been demonstrated in vitro in hippocampal slices from Negr1-deficient mice. In this study, we expanded on these findings by investigating the behavioural response to NMDA receptor antagonism, expression of NMDA receptor subunits, and kynurenine pathway metabolites in a Negr1-deficient mouse model. Male and female wild-type and Negr1-deficient mice received daily injections of MK-801, a non-competitive NMDA receptor antagonist, until behavioural tolerance developed in the open field test (after 9 days in males and 5 days in females). In drug-naive animals, acute MK-801 administration (0.2 mg/kg) elicited a stronger motor response in Negr1-deficient males compared to wild-type controls. However, with repeated dosing, Negr1-deficient males exhibited a blunted behavioural response and attenuated progression of rapid behavioural tolerance during every-second-day MK-801 administration, suggesting altered receptor sensitivity. Gene expression analysis revealed sex- and brain region-specific changes in NMDA receptor subunit expression. Additionally, kynurenine pathway metabolites showed genotype- and sex-dependent alterations. These findings suggest that NEGR1 protein modulates NMDA receptor function and tryptophan metabolism in a sex-dependent manner, highlighting the importance of considering both genetic background and sex in models of glutamatergic dysfunction relevant to neuropsychiatric disorders.

The online version contains supplementary material available at 10.1038/s41598-026-35968-7.