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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