Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes

Abstract

Context Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. Objectives To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Design Case-control postmortem and clinical study. Setting Maryland Brain Collection, outpatient clinics. Participants Postmortem specimens from schizophrenia patients (n=32) and control donors (n=32) and a clinical sample of schizophrenia patients (n=248) and healthy controls (n=228). Main Outcome Measures Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). Results In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Conclusion Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

“…Conceivably, the relative effects of KA versus 3HK and QA are dependent on the type of the disorder under study (eg, schizophrenia versus primary MDD), the nature of the inflammatory stimulus, and as yet uncharacterized molecular actors. Reports indicative of elevations of KA in schizophrenia or BD with psychosis (Olsson et al, 2012;Wonodi et al, 2011) may be particularly relevant as elevations in KA concentrations may potentiate dopaminergic neurotransmission potentially explaining the putative link with psychosis (Olsson et al, 2009). …”

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

“…Impaired KMO function has been implicated in the pathophysiology of schizophrenia (SZ)(3–5), a major psychiatric disorder, which can be traced to abnormal brain development and is characterized by deficits in social and emotional functioning, thought disorder, abnormal perception of reality, and cognitive dysfunction (6). Specifically, postmortem data show that patients with SZ have lower mRNA levels of KMO and decreased KMO activity in the cerebral cortex (4, 7), though cortical 3-HK levels do not appear to be abnormal in SZ (8). Additionally, the non-synonymous single nucleotide polymorphism (SNP) rs2275163 in the gene encoding KMO - originally identified and cautiously linked to SZ by Aoyama and collaborators (9) – is associated with two established SZ endophenotypes, namely impairments in smooth pursuit eye movement and visuospatial working memory (7).…”

“…Specifically, postmortem data show that patients with SZ have lower mRNA levels of KMO and decreased KMO activity in the cerebral cortex (4, 7), though cortical 3-HK levels do not appear to be abnormal in SZ (8). Additionally, the non-synonymous single nucleotide polymorphism (SNP) rs2275163 in the gene encoding KMO - originally identified and cautiously linked to SZ by Aoyama and collaborators (9) – is associated with two established SZ endophenotypes, namely impairments in smooth pursuit eye movement and visuospatial working memory (7). In patients with bipolar disorder, a second polymorphism in the KMO gene (rs1053230) is associated with reduced KMO expression in the hippocampus and in lymphoblastoid cell lines, with higher cerebrospinal fluid (CSF) KYNA concentrations in individuals with a history of psychosis (3).…”

Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid

“…Brain KYNA is an astrocyte-derived metabolite of the kynurenine pathway of tryptophan degradation and its dysregulation is thought to be implicated in schizophrenia (Plitman et al, 2017). Evidence for such a pathophysiological link arises from studies showing increased levels of KYNA in the brain and CSF (Erhardt et al, 2001;Linderholm et al, 2012), and abnormal expression and activity of key kynurenine pathway enzymes in the brain (Miller et al, 2004;Wonodi et al, 2011) of patients with schizophrenia. Certainly, a causal link between relatively modest elevations of cortical KYNA and deficits in executive function has been well documented in preclinical studies (Chess et al, 2007;Akagbosu et al, 2012;Alexander et al, , 2013.…”