title: Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Case-control postmortem and clinical study.
  
  
  METHODS
  Maryland Brain Collection, outpatient clinics.
  
  
  METHODS
  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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.
authors: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228. iwonodi@mprc.umaryland.edu
authors: Ikwunga
authors: I
authors: Wonodi
authors: O Colin
authors: OC
authors: Stine
authors: Korrapati V
authors: KV
authors: Sathyasaikumar
authors: Rosalinda C
authors: RC
authors: Roberts
authors: Braxton D
authors: BD
authors: Mitchell
authors: L Elliot
authors: LE
authors: Hong
authors: Yasushi
authors: Y
authors: Kajii
authors: Gunvant K
authors: GK
authors: Thaker
authors: Robert
authors: R
authors: Schwarcz
mesh_terms: D000328:Adult; D001923:Brain Chemistry; D016022:Case-Control Studies; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007736:Kynurenic Acid / Q000032:analysis / Q000134:cerebrospinal fluid; D050601:Kynurenine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009801:Oculomotor Muscles / Q000502:physiology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012559:Schizophrenia / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid