title: Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.
abstract: BACKGROUND
  Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia.
  
  
  METHODS
  In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo-/-) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia.
  
  
  RESULTS
  Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo-/-mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo-/-mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo-/-mice showed potentiated horizontal activity in the open field paradigm.
  
  
  CONCLUSIONS
  Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Ana
authors.initials: A
authors.lastname: Pocivavsek
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Repici
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xi-Cong
authors.initials: XC
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Imbeault
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Maddison
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Marian A R
authors.initials: MAR
authors.lastname: Thomas
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Smalley
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Larsson
authors.affiliation: KynuRex, San Francisco, California.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: rschwarc@mprc.umaryland.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000235:genetics* / Q000523:psychology*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology
chemical_list: D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid; D003913:Dextroamphetamine
keywords: Anxiety; Cognition; Kynurenic acid; Locomotor activity; Schizophrenia; Social interaction