TY - JOUR
T1 - Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
AU - Parrott, J. M.
AU - Redus, L.
AU - Santana-Coelho, D.
AU - Morales, J.
AU - Gao, X.
AU - O'Connor, J. C.
N1 - Funding Information:
JCO'C has received funding from Janssen Research and Development for work that is not related to the material presented or discussed in the article submitted for consideration. He has also received funding from the National Institute of Mental Health (R01MH090127), the National Center for Advancing Translational Studies (UL1TR001120) and the Texas Higher Education Coordinating Board (003659-0010¬2013). JMP has received funding from the National Institute of Mental Health (1F31MH102070-01A1). The remaining authors declare no conflicts of interest.
Funding Information:
JCO’C has received funding from Janssen Research and Development for work that is not related to the material presented or discussed in the article submitted for consideration. He has also received funding from the National Institute of Mental Health (R01MH090127), the National Center for Advancing Translational Studies (UL1TR001120) and the Texas Higher Education Coordinating Board (003659-0010-2013). JMP has received funding from the National Institute of Mental Health (1F31MH102070-01A1). The remaining authors declare no conflicts of interest.
Funding Information:
All animal care and use was carried out in accord with the Guide for the Care and Use of Laboratory Animals, 8th edition (NRC) and approved by the Institutional Animal Care and Use Committee at The University of Texas Health Science Center at San Antonio. General health of the mice was monitored daily. Knockout first, conditional ready KMO and HAAO transgenic mice (Kmotm1a(KOMP)Wtsi and Haaotm1a(KOMP)Wtsi) on a C57BL/6N background were designed and generated by the Mouse Biology Program (MBP, www.mousebiology.org) at the University of California Davis (UC Davis). The MBP was supported by the Knock-Out Mouse Project (KOMP), a trans-NIH initiative, and the CSD Consortium, composed of the Children’s Hospital Oakland Research Institute (CHORI), the Wellcome Trust Sanger Institute and UC Davis. Vectors, embryonic stem cells and gene information related to these mouse strains are available at the KOMP Repository (www. komp.org) maintained by UC Davis and CHORI.
Funding Information:
The mouse strain used for this research project was generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (www. komp.org). NIH grants to Velocigene at Regeneron Inc (U01HG004085) and the CSD Consortium (U01HG004080) funded the generation of gene-targeted ES cells for 8500 genes in the KOMP Program and archived and distributed by the KOMP Repository at UC Davis and CHORI (U42RR024244). For more information or to obtain KOMP products go to www.komp.org or email service@komp.org. We specially thank Susan T. Weintraub at the University of Texas Health Science Center at San Antonio’s Mass Spectrometry Core Facilities for her assistance with LC/MS method design, sample preparation, sample analysis and data collection. Mass spectrometry analyses were conducted on instrumentation obtained with funds from NIH Grant 1S10OD016417-01 to STW.
Publisher Copyright:
© The Author(s) 2016.
PY - 2016
Y1 - 2016
N2 - The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO-/-) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg-1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO-/- mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO-/- mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO- dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.
AB - The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO-/-) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg-1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO-/- mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO-/- mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO- dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.
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U2 - 10.1038/TP.2016.200
DO - 10.1038/TP.2016.200
M3 - Article
C2 - 27754481
AN - SCOPUS:84999947490
VL - 6
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 10
M1 - e918
ER -