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.
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 schizophreniapatients. 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 schizophreniapatients (n = 32) and control donors (n = 32) and a clinical sample of schizophreniapatients (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 schizophreniapatients 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 schizophreniapatients. In the clinical sample, KMOrs2275163 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.
Authors: Sherry Leonard; Judith Gault; Jan Hopkins; Judith Logel; Ruby Vianzon; Margaret Short; Carla Drebing; Ralph Berger; Diana Venn; Pinkhas Sirota; Gary Zerbe; Ann Olincy; Randal G Ross; Lawrence E Adler; Robert Freedman Journal: Arch Gen Psychiatry Date: 2002-12
Authors: Linnéa Asp; Maria Holtze; Susan B Powell; Håkan Karlsson; Sophie Erhardt Journal: Int J Neuropsychopharmacol Date: 2009-07-17 Impact factor: 5.176
Authors: L Elliot Hong; Kathleen A Turano; Hugh O'Neill; Lei Hao; Ikwunga Wonodi; Robert P McMahon; Amie Elliott; Gunvant K Thaker Journal: Biol Psychiatry Date: 2007-07-30 Impact factor: 13.382
Authors: Cathryn M Lewis; Douglas F Levinson; Lesley H Wise; Lynn E DeLisi; Richard E Straub; Iiris Hovatta; Nigel M Williams; Sibylle G Schwab; Ann E Pulver; Stephen V Faraone; Linda M Brzustowicz; Charles A Kaufmann; David L Garver; Hugh M D Gurling; Eva Lindholm; Hilary Coon; Hans W Moises; William Byerley; Sarah H Shaw; Andrea Mesen; Robin Sherrington; F Anthony O'Neill; Dermot Walsh; Kenneth S Kendler; Jesper Ekelund; Tiina Paunio; Jouko Lönnqvist; Leena Peltonen; Michael C O'Donovan; Michael J Owen; Dieter B Wildenauer; Wolfgang Maier; Gerald Nestadt; Jean-Louis Blouin; Stylianos E Antonarakis; Bryan J Mowry; Jeremy M Silverman; Raymond R Crowe; C Robert Cloninger; Ming T Tsuang; Dolores Malaspina; Jill M Harkavy-Friedman; Dragan M Svrakic; Anne S Bassett; Jennifer Holcomb; Gursharan Kalsi; Andrew McQuillin; Jon Brynjolfson; Thordur Sigmundsson; Hannes Petursson; Elena Jazin; Tomas Zoëga; Tomas Helgason Journal: Am J Hum Genet Date: 2003-06-11 Impact factor: 11.025
Authors: Rebekka Lencer; Jeffrey R Bishop; Margret S H Harris; James L Reilly; Shitalben Patel; Rick Kittles; Konasale M Prasad; Vishwajit L Nimgaonkar; Matcheri S Keshavan; John A Sweeney Journal: Eur Arch Psychiatry Clin Neurosci Date: 2013-10-25 Impact factor: 5.270
Authors: Olaoluwa Okusaga; Dietmar Fuchs; Gloria Reeves; Ina Giegling; Annette M Hartmann; Bettina Konte; Marion Friedl; Maureen Groer; Thomas B Cook; Kelly A Stearns-Yoder; Janardan P Pandey; Deanna L Kelly; Andrew J Hoisington; Christopher A Lowry; William W Eaton; Lisa A Brenner; Dan Rujescu; Teodor T Postolache Journal: Psychosom Med Date: 2016-10 Impact factor: 4.312
Authors: Eden Flores-Barrera; Daniel R Thomases; Daryn K Cass; Ajay Bhandari; Robert Schwarcz; John P Bruno; Kuei Y Tseng Journal: J Neurosci Date: 2017-07-20 Impact factor: 6.167
Authors: Michelle L Pershing; David Phenis; Valentina Valentini; Ana Pocivavsek; Derick H Lindquist; Robert Schwarcz; John P Bruno Journal: Psychopharmacology (Berl) Date: 2016-08-16 Impact factor: 4.530
Authors: Joshua Chiappelli; Ana Pocivavsek; Katie L Nugent; Francesca M Notarangelo; Peter Kochunov; Laura M Rowland; Robert Schwarcz; L Elliot Hong Journal: JAMA Psychiatry Date: 2014-07-01 Impact factor: 21.596