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Dysregulation of the Kynurenine Pathway in Psychotic Disorders – Immunological Aspects

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Dysregulation of the Kynurenine Pathway in Psychotic Disorders – Immunological Aspects From the Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden DYSREGULATION OF THE KYNURENINE PATHWAY IN PSYCHOTIC DISORDERS – IMMUNOLOGICAL ASPECTS Magdalena Kegel Stockholm 2014 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Åtta.45 © Magdalena Kegel, 2014 ISBN 978-91-7549-695-5 Institutionen för fysiologi och farmakologi DYSREGULATION OF THE KYNURENINE PATHWAY IN PSYCHOTIC DISORDERS – IMMUNOLOGICAL ASPECTS AKADEMISK AVHANDLING som för avläggande av medicine doktorsexamen vid Karolinska Institutet offentligen försvaras i Farmakologisalen; Nanna Svartz väg 2, Karolinska Institutet, Solna Fredagen den 24 oktober, 2014, kl 09.00 av Magdalena Kegel Huvudhandledare: Fakultetsopponent: Docent Sophie Erhardt Professor Norbert Müller Karolinska Institutet Ludwig-Maximilians-University, Institutionen för fysiologi och farmakologi Clinic and Polyclinic for Psychiatry and Psychotherapy Bihandledare: Dr Camilla I. Svensson Betygsnämnd: Karolinska Institutet Docent Robert Bodén Institutionen för fysiologi och farmakologi Uppsala Universitet Institutionen för Neurovetenskap Bihandledare: Professor Mikael Landén Docent Gunnar Schulte Karolinska Institutet Karolinska Institutet Institutionen för medicinsk epidemiologi Institutionen för fysiologi och farmakologi och biostatistik Professor Nikolaos Venizelos Örebro Universitet Institutionen för hälsovetenskap och medicin ABSTRACT Kynurenic acid (KYNA), a metabolite of the kynurenine pathway, is emerging as a key factor in the development of psychotic disorders. Increased levels of KYNA are found in the brain and cerebrospinal fluid (CSF) of patients with schizophrenia and bipolar disorder, and are associated to psychotic symptoms. The unique pharmacological profile of KYNA allows it to exert actions on all the main neurotransmitter systems of the brain. The kynurenine pathway is under immunological control and can be induced by inflammatory signaling, hence linking findings of an immune involvement in psychotic disorders with established hypotheses of dopamine and glutamate in schizophrenia. KYNA has also been linked to impaired cognitive functioning, often accompanying psychotic disorders. Along this background, we set out to further investigate the kynurenine pathway and its induction by immune signaling, in the main psychotic disorders schizophrenia and bipolar disorder. Starting with a GWAS against CSF levels of KYNA, and with the aid of clinical association studies, post mortem analyses and cell culture experiments, we identified a gene variant associated to a decreased function of SNX7 in patients with bipolar disorder. SNX7 was shown to influence the activity of caspase-8, an activator of interleukin (IL)-1β. Using primary human astrocyte cultures, we show that IL-1β selectively induces TDO and hence increases the production of KYNA. In this study, KYNA was also associated to dopamine signaling, psychotic symptoms and impaired executive functions in patients with bipolar disorder. In patients with schizophrenia, we show that levels of CSF quinolinic acid (QUIN), produced in the other branch of the kynurenine pathway, are not elevated, but the QUIN/KYNA ratio is lowered. These findings suggest an imbalance in the upregulated kynurenine pathway in schizophrenia. Further tryptophan, along with the kynurenine metabolites KYNA and QUIN, the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA), and the cytokines IL-6, IL-8 and tumor necrosis factor (TNF)-α were investigated in the CSF of a cohort of twins with various psychiatric morbidity. Data presented here support a considerable environmental contribution to the levels of these factors. Associations between CSF levels of KYNA and levels of HVA as well as 5-HIAA were observed, as were associations between these CSF metabolites and psychopathology measures, extended to enlace schizotypal traits also present in relatives of patients with psychotic disorders. Finally, we investigated if dermal ex vivo fibroblasts could serve as a model for studying the kynurenine pathway. All pathway enzymes were indeed expressed by the fibroblasts. KYNA was produced following stimulation with typical pathway inducing cytokines, i.e. interferon-γ and TNF-α, hence indicating the possibility to develop a model of easily accessible cells for studies of molecular and genetic aspects of psychotic disorders. Taken together, the data presented in this thesis strengthens the position of KYNA as a highly interesting target for further studies of psychotic disorders as well as for future therapeutic interventions. These data do not only confirm prior studies implicating a role for KYNA in psychotic disorders, but contributes with in-depth knowledge of potential molecular mechanisms linking a genetic makeup to aberrant immune signaling, CSF KYNA levels, psychotic symptoms and impaired cognitive function in patients with psychotic disorders. LIST OF PUBLICATIONS I. Carl Sellgren*, MAGDALENA E. KEGEL*, Sarah E. Bergen, Carl Johan Ekman, Sara Olsson, Markus Larsson, Marquis P. Vawter, Martin Schalling, Lena Backlund, Patrick F. Sullivan, Pamela Sklar, Jordan W. Smoller, Patrik K.E. Magnusson, Christina M. Hultman, Lilian Walther-Jallow, Camilla I. Svensson, Paul Lichtenstein, Göran Engberg, Sophie Erhardt, Mikael Landén. An inflammatory pathway linked to psychosis in bipolar disorder. Submitted to NEURON. *These authors contributed equally to this work. II. MAGDALENA E. Kegel, Maria Bhat, Elisabeth Skogh, Martin Samuelsson, Kristina Lundberg, Marja-Liisa Dahl, Carl Sellgren, Lilly Schwieler, Göran Engberg, Ina Schuppe-Koistinen, Sophie Erhardt. Imbalanced kynurenine pathway in schizophrenia. Accepted for publication in International Journal of tryptophan research. III. Linnéa Asp, Anne-Sofie Johansson, Amandeep Mann, Björn Owe-Larsson, Ewa M Urbanska, Tomasz Kocki, MAGDALENA KEGEL, Göran Engberg, Gabriella BS Lundkvist and Håkan Karlsson. Effects of pro-inflammatory cytokines on expression of kynurenine pathway enzymes in human dermal fibroblasts. Journal of Inflammation, 2011, 8:25. IV. MAGDALENA E. KEGEL, Viktoria Johansson, Lennart Wetterberg, Maria Bhat, Lilly Schwieler, Tyrone Cannon, Ina Schuppe-Koistinen, Göran Engberg, Mikael Landén, Christina M. Hultman, Sophie Erhardt. Kynurenic acid, HVA and schizotypal personality traits in twin pairs with psychiatric morbidity. Manuscript TABLE OF CONTENTS 1 Introduction .............................................................................................................................. 9 1.1 Schizophrenia ................................................................................................................... 9 1.2 Bipolar Disorder ............................................................................................................. 12 1.3 Differences and similarities between schizophrenia and Bipolar Disorder .................. 14 1.4 The kynurenine pathway ................................................................................................ 15 1.4.1 Neurochemical properties of kynurenines .............................................................. 17 1.4.2 Regulation of the kynurenine pathway ................................................................... 18 1.4.3 Regulation of the kynurenine pathway by immunological stimuli ........................ 19 1.4.4 Physiological significance of the kynurenine pathway .......................................... 21 1.4.5 The kynurenine pathway in psychiatric disorders .................................................. 23 1.4.6 The kynurenic acid hypothesis of schizophrenia .................................................... 25 1.5 Immune processes and neuroinflammation ................................................................... 27 1.5.1 Immune system involvement in psychotic disorders ............................................. 30 1.6 Genetic aspects of psychotic disorders .......................................................................... 32 2 Aims ....................................................................................................................................... 34 3 Materials and methods ........................................................................................................... 35 3.1 Ethics .............................................................................................................................. 35 3.2 Cell culture studies ......................................................................................................... 35 3.2.1 Cytokines and antibodies ........................................................................................ 35 3.2.2 Fibroblast Cultures .................................................................................................. 36 3.2.3 Human Astrocyte Culture ....................................................................................... 36 3.2.4 RNA extraction and reverse transcription .............................................................. 37 3.2.5 Real-time PCR and data analysis ............................................................................ 37 3.2.6 Protein extraction and Western Blotting ................................................................. 39 3.2.7 Immunocytochemistry ............................................................................................ 39 3.3 Human subjects .............................................................................................................
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