Background: Several studies suggest a pathophysiologically relevant association between increased brain levels of the neuroinhibitory tryptophan metabolite kynurenic acid and cognitive dysfunctions in people with schizophrenia. Elevated kynurenic acid in schizophrenia may be secondary to a genetic alteration of kynurenine 3-monooxygenase, a pivotal enzyme in the kynurenine pathway of tryptophan degradation. In rats, prenatal exposure to kynurenine, the direct bioprecursor of kynurenic acid, induces cognitive impairments reminiscent of schizophrenia in adulthood, suggesting a developmental dimension to the link between kynurenic acid and schizophrenia. Aim: The purpose of this study was to explore the possible impact of the maternal genotype on kynurenine pathway metabolism. Methods: We exposed pregnant wild-type (Kmo +/+ ) and heterozygous (Kmo +/− ) mice to kynurenine (10 mg/day) during the last week of gestation and determined the levels of kynurenic acid and two other neuroactive kynurenine pathway metabolites, 3-hydroxykynurenine and quinolinic acid, in fetal brain and placenta on embryonic day 17/18. Results: Maternal kynurenine treatment raised kynurenic acid levels significantly more in the brain of heterozygous offspring of Kmo +/− than in the brain of Kmo +/+ offspring. Conversely, 3-hydroxykynurenine and quinolinic acid levels in the fetal brain tended to be lower in heterozygous animals derived from kynurenine-treated Kmo +/− mice than in corresponding Kmo +/+ offspring. Genotype-related effects on the placenta were qualitatively similar but less pronounced. Kynurenine treatment also caused a preferential elevation in cerebral kynurenic acid levels in Kmo +/− compared to Kmo +/+ dams. Conclusions: The disproportionate kynurenic acid increase in the brain of Kmo +/− animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia.

Maternal genotype determines kynurenic acid levels in the fetal brain: Implications for the pathophysiology of schizophrenia

Beggiato S.;
2018

Abstract

Background: Several studies suggest a pathophysiologically relevant association between increased brain levels of the neuroinhibitory tryptophan metabolite kynurenic acid and cognitive dysfunctions in people with schizophrenia. Elevated kynurenic acid in schizophrenia may be secondary to a genetic alteration of kynurenine 3-monooxygenase, a pivotal enzyme in the kynurenine pathway of tryptophan degradation. In rats, prenatal exposure to kynurenine, the direct bioprecursor of kynurenic acid, induces cognitive impairments reminiscent of schizophrenia in adulthood, suggesting a developmental dimension to the link between kynurenic acid and schizophrenia. Aim: The purpose of this study was to explore the possible impact of the maternal genotype on kynurenine pathway metabolism. Methods: We exposed pregnant wild-type (Kmo +/+ ) and heterozygous (Kmo +/− ) mice to kynurenine (10 mg/day) during the last week of gestation and determined the levels of kynurenic acid and two other neuroactive kynurenine pathway metabolites, 3-hydroxykynurenine and quinolinic acid, in fetal brain and placenta on embryonic day 17/18. Results: Maternal kynurenine treatment raised kynurenic acid levels significantly more in the brain of heterozygous offspring of Kmo +/− than in the brain of Kmo +/+ offspring. Conversely, 3-hydroxykynurenine and quinolinic acid levels in the fetal brain tended to be lower in heterozygous animals derived from kynurenine-treated Kmo +/− mice than in corresponding Kmo +/+ offspring. Genotype-related effects on the placenta were qualitatively similar but less pronounced. Kynurenine treatment also caused a preferential elevation in cerebral kynurenic acid levels in Kmo +/− compared to Kmo +/+ dams. Conclusions: The disproportionate kynurenic acid increase in the brain of Kmo +/− animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11564/725262
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