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<p>The <i>NEGR1</i> gene has been implicated in several psychiatric disorders, and increased NMDA receptor binding density has been demonstrated in vitro in hippocampal slices from <i>Negr1</i>-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 <i>Negr1</i>-deficient mouse model. Male and female wild-type and <i>Negr1</i>-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&#xa0;mg/kg) elicited a stronger motor response in <i>Negr1</i>-deficient males compared to wild-type controls. However, with repeated dosing, <i>Negr1</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Carolin Kuuskmäe,
  • Kaie Mikheim,
  • Narges Mohammadrahimi,
  • Kalle Kilk,
  • Maria Kaare,
  • Mohan Jayaram,
  • German Ilnitski,
  • Este Leidmaa,
  • Mari-Anne Philips,
  • Eero Vasar

摘要

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.