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

Sophie Erhardt, Ana Pocivavsek, Mariaelena Repici, Xi-Cong Liu, Sophie Imbeault, Daniel C Maddison, Marian A R Thomas, Joshua L Smalley, Markus K Larsson, Paul J Muchowski, Flaviano Giorgini, Robert Schwarcz

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)756-765
Number of pages10
JournalBiological Psychiatry
Volume82
Issue number10
Early online date16 Dec 2016
DOIs
Publication statusPublished - 15 Nov 2017

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Kynurenine 3-Monooxygenase
Knockout Mice
Psychotic Disorders
Kynurenic Acid
Kynurenine
Schizophrenia
Cerebellum
Cerebrum
Amphetamine
Interpersonal Relations
N-Methyl-D-Aspartate Receptors
Psychopathology
Cerebral Cortex
Genes
Acetylcholine
Psychiatry
Anxiety
Central Nervous System
Genome

Bibliographical note

© 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

  • Animals
  • Cerebellum/metabolism
  • Cerebral Cortex/metabolism
  • Dextroamphetamine/pharmacology
  • Kynurenic Acid/metabolism
  • Kynurenine 3-Monooxygenase/deficiency
  • Mice
  • Mice, Knockout
  • Motor Activity/drug effects
  • Psychotic Disorders/genetics
  • Schizophrenia/genetics
  • Schizophrenic Psychology

Cite this

Erhardt, Sophie ; Pocivavsek, Ana ; Repici, Mariaelena ; Liu, Xi-Cong ; Imbeault, Sophie ; Maddison, Daniel C ; Thomas, Marian A R ; Smalley, Joshua L ; Larsson, Markus K ; Muchowski, Paul J ; Giorgini, Flaviano ; Schwarcz, Robert. / Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice : Relevance to Psychotic Disorders. In: Biological Psychiatry. 2017 ; Vol. 82, No. 10. pp. 756-765.
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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.",
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author = "Sophie Erhardt and Ana Pocivavsek and Mariaelena Repici and Xi-Cong Liu and Sophie Imbeault and Maddison, {Daniel C} and Thomas, {Marian A R} and Smalley, {Joshua L} and Larsson, {Markus K} and Muchowski, {Paul J} and Flaviano Giorgini and Robert Schwarcz",
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Erhardt, S, Pocivavsek, A, Repici, M, Liu, X-C, Imbeault, S, Maddison, DC, Thomas, MAR, Smalley, JL, Larsson, MK, Muchowski, PJ, Giorgini, F & Schwarcz, R 2017, 'Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders', Biological Psychiatry, vol. 82, no. 10, pp. 756-765. https://doi.org/10.1016/j.biopsych.2016.12.011

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice : Relevance to Psychotic Disorders. / Erhardt, Sophie; Pocivavsek, Ana; Repici, Mariaelena; Liu, Xi-Cong; Imbeault, Sophie; Maddison, Daniel C; Thomas, Marian A R; Smalley, Joshua L; Larsson, Markus K; Muchowski, Paul J; Giorgini, Flaviano; Schwarcz, Robert.

In: Biological Psychiatry, Vol. 82, No. 10, 15.11.2017, p. 756-765.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice

T2 - Relevance to Psychotic Disorders

AU - Erhardt, Sophie

AU - Pocivavsek, Ana

AU - Repici, Mariaelena

AU - Liu, Xi-Cong

AU - Imbeault, Sophie

AU - Maddison, Daniel C

AU - Thomas, Marian A R

AU - Smalley, Joshua L

AU - Larsson, Markus K

AU - Muchowski, Paul J

AU - Giorgini, Flaviano

AU - Schwarcz, Robert

N1 - © 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

PY - 2017/11/15

Y1 - 2017/11/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cerebellum/metabolism

KW - Cerebral Cortex/metabolism

KW - Dextroamphetamine/pharmacology

KW - Kynurenic Acid/metabolism

KW - Kynurenine 3-Monooxygenase/deficiency

KW - Mice

KW - Mice, Knockout

KW - Motor Activity/drug effects

KW - Psychotic Disorders/genetics

KW - Schizophrenia/genetics

KW - Schizophrenic Psychology

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U2 - 10.1016/j.biopsych.2016.12.011

DO - 10.1016/j.biopsych.2016.12.011

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