Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Abstract

IntroductionIn recent years, the general view of the pathophysiology of schizophrenia (i.e., disturbances in dopamine [DA] transmission) has been expanded to also involve a glutamatergic dysfunction of the brain. Thus, clinical observations show that systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., phencyclidine [PCP] and ketamine) evokes schizophrenia-like symptoms in healthy individuals and provokes symptoms in patients with schizophrenia. [1][2][3] Furthermore, the glutamate deficiency theory has gained some support from genetic findings. 4 A hypoglutamatergic state of the brain can also be achieved by elevation of the endogenous NMDA receptor antagonist kynurenic acid (KYNA).5 Indeed, increased concentrations of KYNA have been found in the cerebrospinal fluid (CSF) and in the postmortem brains of patients with schizophrenia.6-8 Kynurenic acid is a metabolite of tryptophan ( Fig. 1) and acts as an antagonist at the glycine coagonist site and the glutamate recognition site of the NMDA receptor.9-12 Additionally, KYNA blocks the α7* nicotinic receptor at low concentrations.13 Elevated levels of KYNA in the rat brain are associated with . This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine. Methods: We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. Results: We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. Limitations: Given the limited sample size, the results are tentative until replication. Conclusion: Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

“…Indeed any immune challenge to the mother or neonate which results, directly or indirectly, in the activation of central glia or peripheral macrophages, or changes in the levels of cytokines or kynurenines in the fetal or neonatal CNS would alter the balance of quinolinic acid and kynurenic acid concentrations and could significantly affect neural development and plasticity. This proposal is consistent with evidence that genetic abnormalities of the kynurenine pathway are linked to disorders such as schizophrenia (Miller et al, 2006;Holtze et al, 2012).…”

Imbalanced Kynurenine Pathway in Schizophrenia

“…In a situation where l -kynurenine is elevated (eg, by induction of TDO) such a limitation of KMO might guard against excessive production of QUIN. A suboptimal function of KMO could also present an explanatory mechanism of the observed increase in KYNA but not in QUIN 7,8,39. Such a scenario would thus shunt the metabolism of l -kynurenine toward formation of KYNA, which indeed is observed in the present study.…”

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia

“…Exploratory analyses in European-Americans in the current sample showed an effect of the functional KMO Arg 452 Cys variant on global cognitive composite score in pooled patients and controls, although there was no genotype by diagnosis interaction. Nevertheless, this trend level effect accords with reports showing effects of this variant on KMO expression and KYNA levels in European samples (Holtze et al, 2012; Lavebratt et al, 2014). …”

“…In the present study, we hypothesized that the rs2275163C>T risk allele, which was associated with reduced KMO messenger RNA (mRNA) expression (which would shunt KP metabolism towards enhanced KYNA formation) in our original report, would be associated with poor cognitive performance. Because a second non-synonymous variant in KMO , the C ( Arg 452 ) allele of rs1053230>NT (Arg 452 Cys) has also recently been associated with reduced KMO mRNA expression in brain and lymphoblastoid tissues, and with increased KYNA levels in cerebrospinal fluid (Holtze et al, 2012; Lavebratt et al, 2014), we additionally tested as a secondary aim, the association of this SNP with cognitive function in our sample. Lastly, we explored the effect of the KMO risk allele on P50 gating.…”