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Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.

Authors
  • Kindler, Jochen1, 2, 3
  • Lim, Chai K4
  • Weickert, Cynthia Shannon1, 2, 5
  • Boerrigter, Danny2, 5
  • Galletly, Cherrie6, 7, 8
  • Liu, Dennis6, 8
  • Jacobs, Kelly R4
  • Balzan, Ryan9
  • Bruggemann, Jason1, 2
  • O'Donnell, Maryanne1, 10
  • Lenroot, Rhoshel1, 2, 5
  • Guillemin, Gilles J4
  • Weickert, Thomas W11, 12, 13
  • 1 School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia. , (Australia)
  • 2 Neuroscience Research Australia, Randwick, NSW, 2031, Australia. , (Australia)
  • 3 University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, 3000, Bern, Switzerland. , (Switzerland)
  • 4 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia. , (Australia)
  • 5 Schizophrenia Research Institute, Randwick, NSW, 2010, Australia. , (Australia)
  • 6 Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia. , (Australia)
  • 7 Ramsay Health Care (SA) Mental Health, Adelaide, SA, Australia. , (Australia)
  • 8 Northern Adelaide Local Health Network, Adelaide, SA, Australia. , (Australia)
  • 9 College of Education, Psychology, and Social Work, Flinders University, Adelaide, SA, Australia. , (Australia)
  • 10 Kiloh Centre, Prince of Wales Hospital, Randwick, NSW, Australia. , (Australia)
  • 11 School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia. [email protected] , (Australia)
  • 12 Neuroscience Research Australia, Randwick, NSW, 2031, Australia. [email protected] , (Australia)
  • 13 Schizophrenia Research Institute, Randwick, NSW, 2010, Australia. [email protected] , (Australia)
Type
Published Article
Journal
Molecular psychiatry
Publication Date
Nov 01, 2020
Volume
25
Issue
11
Pages
2860–2872
Identifiers
DOI: 10.1038/s41380-019-0401-9
PMID: 30940904
Source
Medline
Language
English
License
Unknown

Abstract

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

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