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

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posted on 2019-01-31, 11:22 authored by S Beggiato, FM Notarangelo, KV Sathyasaikumar, F Giorgini, R Schwarcz
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.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grant P50 MH103222 from the National Institute for Mental Health.

History

Citation

Journal of Psychopharmacology, 2018, Volume: 32 issue: 11, page(s): 1223-1232

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology

Version

  • AM (Accepted Manuscript)

Published in

Journal of Psychopharmacology

Publisher

SAGE Publications (UK and US) for British Association for Psychopharmacology

eissn

1461-7285

Copyright date

2018

Available date

2019-01-31

Publisher version

https://journals.sagepub.com/doi/10.1177/0269881118805492

Language

en

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