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

Sarah Beggiato,Flaviano Giorgini,Francesca M Notarangelo,Robert Schwarcz,Korrapati V Sathyasaikumar

doi:10.1177/0269881118805492

Sarah Beggiato, Flaviano Giorgini + Show 3 more

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https://doi.org/10.1177/0269881118805492

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Abstract

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. The purpose of this study was to explore the possible impact of the maternal genotype on kynurenine pathway metabolism. 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. 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. 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.

Highlights

In both animals and humans, even subtle changes in the intrauterine milieu can lead to permanent alterations in brain structure and cognitive functions in the offspring (Debnath et al, 2015; Seidman et al, 2000; Stolp et al, 2012)
Elevated kynurenic acid (KYNA) in schizophrenia may be secondary to a genetic alteration of kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation
The disproportionate KYNA increase in the brain of Kmo+/- animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia

Summary

Introduction

In both animals and humans, even subtle changes in the intrauterine milieu can lead to permanent alterations in brain structure and cognitive functions in the offspring (Debnath et al, 2015; Seidman et al, 2000; Stolp et al, 2012). Increased brain KYNA levels cause deficits in cognitive functions, including impairments in working memory, sensorimotor gating and attentional processing, in adult rodents (Akagbosu et al, 2012; Chess and Bucci, 2006; Chess et al, 2007; DeAngeli et al, 2014; Erhardt et al, 2004; Pershing et al, 2015; Shepard et al, 2003) These observations are provocative, as fluctuations in KYNA normally control glutamatergic and cholinergic, as well as dopaminergic and GABAergic, neurotransmission in the adult brain (see Pocivavsek et al, 2016 for review) and may serve critical roles in normal brain development (Ben-Ari et al, 1997; Dwyer et al, 2009). Aim To explore the possible impact of the maternal genotype on KP metabolism

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