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

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.