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.
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The data that support the findings of this study are available upon reasonable request to the corresponding author.
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This research was funded by the investigation grant PRG2544 from the Estonian Research Council (E.V.).
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Conceptualisation: M-A.P., E.V.; Methodology: C.K., K.M., K.K., M.K., M.J., N.M., G.I., E.L., M-A.P; Analysis: C.K, K.M., K.K., M-A.P.; Writing—original draft preparation: C.K., M-A.P., E.V.; Writing—review and editing: C.K., K.M., K.K., M.K., M.J., N.M., G.I., E.L., M-A.P, E.V.; Prepared figures: C.K, M-A.P. Funding acquisition: M-A.P., E.V. All authors critically revised the manuscript for intellectual content and approved the final version for publication.
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All animal procedures were approved by the local animal ethics committee (Permit No. 150, 27 September 2019) and conducted in accordance with institutional and national guidelines for the care and use of animals. Euthanasia was performed by trained and experienced personnel. Rapid decapitation was used as the method of euthanasia, which is incompatible with life and therefore constitutes confirmation of death prior to disposal of the remains. Full compliance with the ARRIVE guidelines is detailed in the ARRIVE checklist provided at the end of the Supplementary Information.
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Kuuskmäe, C., Mikheim, K., Mohammadrahimi, N. et al. Negr1 deficiency alters glutamate signalling and kynurenine pathway in a mouse model of psychiatric disorders. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35968-7
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DOI: https://doi.org/10.1038/s41598-026-35968-7
