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.
Kuuskmäe et al. (Fri,) studied this question.