Maternal genotype determines kynurenic acid levels in the fetal brain: Implications for the pathophysiology of schizophrenia.
| Autor: | Beggiato S; 1 Department of Life Sciences and Biotechnologies, University of Ferrara, Ferrara, Italy.; 2 Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy., Notarangelo FM; 3 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA., Sathyasaikumar KV; 3 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA., Giorgini F; 4 Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Schwarcz R; 3 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of psychopharmacology (Oxford, England) [J Psychopharmacol] 2018 Nov; Vol. 32 (11), pp. 1223-1232. Date of Electronic Publication: 2018 Oct 24. |
| DOI: | 10.1177/0269881118805492 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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