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

Abstract

Background Several studies suggest a pathophysiologically relevant association between increased brain levels of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA) and cognitive dysfunctions in people with schizophrenia. Elevated 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. In rats, prenatal exposure to kynurenine, the direct bioprecursor of KYNA, induces cognitive impairments reminiscent of schizophrenia in adulthood, suggesting a developmental dimension to the link between KYNA and schizophrenia. Aim To explore the possible impact of the maternal genotype on KP 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 KYNA and two other neuroactive KP metabolites, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), in fetal brain and placenta on embryonic day 17/18. Results Maternal kynurenine treatment raised KYNA levels significantly more in the brain of heterozygous offspring of Kmo +/than in the brain of Kmo +/+ offspring. Conversely, 3-HK and QUIN 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 KYNA levels in Kmo +/compared to Kmo +/+ dams. Conclusions 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.

Effects of inflammation on the kynurenine pathway in schizophrenia — a systematic review

“…These findings raise many questions, such as "what are the most important metabolites that relay inflammation or inflammatory markers and the kynurenine pathway in schizophrenia?" For example, in an animal model of pregnant rats, the deletion of one allele for KMO (KMO +/− ) in the maternal genetic material brought to a disproportionate KYNA increase in the brain of KMO +/− offspring rats, compared to KMO wild-type offspring rats (KMO +/+ ) [84]. As mentioned before, in subjects with schizophrenia, the overproduction of KYNA contributes mainly to an imbalance of Th1/Th2 responses.…”

A single prenatal lipopolysaccharide injection has acute, but not long‐lasting, effects on cerebral kynurenine pathway metabolism in mice

“…They should also be kept in mind in the design of follow‐up studies exploring the role of KP‐related redox processes (Gonzalez Esquivel et al, 2017) and the formation of the neuroactive downstream KP metabolites xanthurenic acid and cinnabarinic acid (Fazio et al, 2017), which were not examined in the present study. Moreover, genetic vulnerability should be considered (Beggiato et al, 2018), and repeated or chronic immune activation either during pregnancy or later in life, too, may have functionally relevant, detrimental impacts on brain KP metabolism (Larsson et al, 2016; Saito et al, 1992).…”

Blockade of KAT II Facilitates LTP in Kynurenine 3-Monooxygenase Depleted Mice

“…Animals were bred in the same room as distinct colonies because maternal KMO genotype may affect kynurenine pathway metabolite production in the offspring. 30 The animals were kept on a 12 hour light-dark cycle (lights on at 06:00) with food and water available ad libitum. For animals undergoing behavioral testing, food restriction to maintain 85% to 90% of free feeding body weight was initiated at least 3 days prior to the start of testing and maintained throughout the test.…”