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Marias Kappa From the Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden THE KYNURENINE PATHWAY AND DEVELOPMENT OF SCHIZOPHRENIA – IMMUNOLOGICAL AND GENETIC ASPECTS Maria Holtze Stockholm 2011 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Larserics Digital Print AB. Cover: Artwork by Christina Holtze and Magnus Knutsson. © Maria Holtze, 2011 ISBN 978-91-7457-469-2 Till Martin ABSTRACT Schizophrenia is a complex disorder with symptoms ranging from hallucinations to poor social functioning and cognitive deficits. Despite decades of research, the etiology of the disease remains puzzling. Genetic aberrations as well as exposure to infection during early life are associated with an increased risk for development of the disease. Recent studies also describe an immune activation in schizophrenia. The immune-related and neuroactive compound kynurenic acid (KYNA), is implicated in the pathophysiology of the disease. KYNA is an astrocyte-derived end product of the kynurenine pathway, the main metabolic route of tryptophan degradation. The aim of the present thesis was to evaluate if disturbances – genetic or caused by early-life infection – in the kynurenine pathway, in particular with regard to KYNA, could contribute to the development of neuropsychiatric disorders, such as schizophrenia. Our results show that infection with the neurotropic influenza A/WSN/33 virus generates a profound induction of the kynurenine pathway in vitro in mouse cell cultures of cortical glial cells and hippocampal neurons, including a robust increase of transcripts encoding IDO and TDO, the enzymes regulating the first and rate-limiting reaction of KYNA production. A systemic injection of the influenza A/WSN/33 virus to wild-type and immune-deficient mice (Tap1-/-), that lack CD8+ T cells, at postnatal day (P) 3 or 4 showed that the infection stimulated the kynurenine pathway in early life. The Tap1-/- mice showed a more persistent induction of the kynurenine pathway enzymes. At P13, infiltration of T cells was observed in the brains of infected wild-type mice, accompanied by a transient elevation of brain KYNA, which was also observed in the Tap1-/- mice. When investigating the long-term behavioral effects of the neonatal infection, we found that Tap1-/-, but not wild-type mice, displayed impaired prepulse inhibition (PPI) in adult life. In adult wild-type mice, the neonatal virus infection was associated with a potentiated D-amphetamine-induced increase in horizontal activity, a behavioral response proposed to reflect schizophrenia. To assess the specific role of brain KYNA in the behavioral abnormalities seen following neonatal infection, brain KYNA was elevated in wild-type mice at P7-16 by the administration of its immediate precursor L- kynurenine. Similar to infected Tap1-/- mice, these mice showed a mild disruption in PPI in adulthood. Furthermore, these mice showed a tendency of hyper-responsiveness to D- amphetamine in locomotor activity. These results indicate that induction of the kynurenine pathway, involving a transient accumulation of brain KYNA in early life, could contribute to behavioral aberrations in adulthood related to schizophrenia. Thus, elevated levels of brain KYNA during a critical period in neurodevelopment might offer a molecular basis of infection as a risk factor for schizophrenia. Furthermore, this thesis reveals that elevated levels of CSF KYNA in human subjects of a Swedish population are associated with a missense single nucleotide polymorphism in the KMO gene, rs1053230. This genetic deficit could result in a dysfunctional KMO enzyme, thereby shunting kynurenine metabolism to KYNA, in line with the increased levels of kynurenine and KYNA observed in patients with schizophrenia. Altogether, this thesis suggests that an early-life CNS induction and/or a genetic deficit of the kynurenine pathway could predispose for development of schizophrenia through the elevation of brain KYNA. LIST OF PUBLICATIONS I. Maria Holtze, Linnéa Asp, Lilly Schwieler, Göran Engberg, Håkan Karlsson. Induction of the kynurenine pathway by neurotropic influenza A virus infection. Journal of Neuroscience Research 2008; 86: 3674-3683 II. Linnéa Asp, Maria Holtze, Susan B. Powell, Håkan Karlsson, Sophie Erhardt. Neonatal infection with neurotropic influenza A virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1-/- mice. International Journal of Neuropsychopharmacology 2010; 13: 475-485 III. Maria Holtze, Susan B. Powell, Linnéa Asp, Håkan Karlsson, Göran Engberg, Sophie Erhardt. Behavioral disturbances in the adult mouse following neonatal virus infection or neonatal kynurenine treatment – role of brain KYNA. Manuscript. IV. Maria Holtze, Peter Saetre, Sophie Erhardt, Lilly Schwieler, Thomas Werge, Thomas Hansen, Jimmi Nielsen, Srdjan Djurovic, Ingrid Melle, Ole A. Andreassen, Håkan Hall, Lars Terenius, Ingrid Agartz, Göran Engberg, Erik G. Jönsson, Martin Schalling. Kynurenine 3-monooxygenase (KMO) polymorphisms in schizophrenia: an association study. Schizophrenia Research 2011; 127: 270-272. V. Maria Holtze, Peter Saetre, Göran Engberg, Lilly Schwieler, Thomas Werge, Ole A. Andreassen, Håkan Hall, Lars Terenius, Ingrid Agartz, Erik G. Jönsson, Martin Schalling, Sophie Erhardt. Kynurenine 3-monooxygenase polymorphisms: relevance for KYNA synthesis in patients with schizophrenia and healthy controls. Journal of Psychiatry & Neuroscience 2011; 36: 100175. E-pub ahead of print. DOI: 10.1503/jpn.100175 TABLE OF CONTENTS 1 Introduction ................................................................................................................. 1 1.1 Schizophrenia .................................................................................................. 1 1.2 Risk factors for the development of schizophrenia ........................................ 2 1.2.1 Environmental influences ............................................................... 2 1.2.2 Genetic aspects ................................................................................ 8 1.3 The kynurenine pathway ............................................................................... 12 1.3.1 Enzymatic steps ............................................................................. 13 1.3.2 Kynurenine pathway induction following immune activation ..... 15 1.3.3 Physiological significance of the kynurenine pathway ................ 18 1.4 Virus infections and CNS immune responses ............................................... 21 1.5 Hypotheses of schizophrenia pathophysiology ............................................. 24 1.5.1 Dopamine in schizophrenia ........................................................... 24 1.5.2 Glutamate in schizophrenia ........................................................... 26 1.5.3 The kynurenic acid hypothesis of schizophrenia .......................... 28 2 Aims of the thesis ...................................................................................................... 31 3 Methodological considerations ................................................................................. 32 3.1 Animals .......................................................................................................... 32 3.2 Drugs .............................................................................................................. 33 3.3 Neonatal treatment ......................................................................................... 33 3.3.1 Influenza A/WSN/33 virus infection of mice ............................... 33 3.3.2 L-kynurenine treatment of mice .................................................... 34 3.4 Influenza A/WSN/33 virus infection of primary cell cultures ..................... 34 3.5 High-performance liquid chromatography ................................................... 35 3.6 Immunofluorescent labeling of T cells ......................................................... 36 3.7 RNA isolation and real-time PCR ................................................................. 36 3.8 Behavioral tests .............................................................................................. 38 3.8.1 Prepulse inhibition ......................................................................... 38 3.8.2 Open field locomotor activity ....................................................... 40 3.9 Human samples ............................................................................................. 41 3.10 Genotyping of human DNA samples .......................................................... 41 4 Results and discussion ............................................................................................... 43 4.1 Influenza virus infection of mice in vitro and in vivo: Induction of the kynurenine pathway ................................................................................................ 43 4.1.1 Effects of the virus infection in mouse brain cell cultures ........... 43 4.1.2 Early-life effects of neonatal virus infection in wild-type and Tap1-/- mouse brain .................................................................................... 46 4.1.3 Behavioral effects in adult mice following neonatal treatment .... 52 4.2 Human Genetic studies .................................................................................. 59 5 General Discussion ...................................................................................................
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