Dysregulation of the kynurenine pathway in psychotic disorders : immunological aspects

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, Goran Engberg, Sophie Erhardt, Mikael Landen. 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, Goran Engberg, Ina Schuppe-Koistinen, Sophie Erhardt. Imbalanced kynurenine pathway in schizophrenia. Accepted for publication in International Journal of tryptophan research. III. Linnea Asp, Anne-Sofie Johansson, Amandeep Mann, Bjorn Owe-Larsson, Ewa M Urbanska, Tomasz Kocki, MAGDALENA KEGEL, Goran Engberg, Gabriella BS Lundkvist and Hakan 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, Goran Engberg, Mikael Landen, Christina M. Hultman, Sophie Erhardt. Kynurenic acid, HVA and schizotypal personality traits in twin pairs with psychiatric morbidity. Manuscript