Bridging immune activation with the kynurenine pathway : implications for psychosis
Author: Larsson, Markus
Date: 2015-06-12
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för fysiologi och farmakologi / Dept of Physiology and Pharmacology
View/ Open:
Thesis (5.503Mb)
Abstract
Kynurenic acid (KYNA), an endogenous N-Methyl-D-aspartic acid receptor (NMDAR) antagonist, is elevated in patients with schizophrenia. In addition, elevated levels of KYNA are associated with activation of the immune system, which also has been implicated in the development and maintenance of psychotic disorders, including schizophrenia.
The aim of this thesis was to further investigate the role of KYNA in the pathophysiology of schizophrenia. Thus, patients with schizophrenia were examined with respect to cerebrospinal fluid (CSF) levels of interleukin (IL)-6, kynurenines, and the functional effects of G protein- coupled receptor kinase 3 (GRK3) expression. Mice administered lipopolysaccharide (LPS), amphetamine, or lacking the immune-regulating enzyme GRK3, were studied with respect to biochemical and functional aberrations associated with schizophrenia.
The elevated CSF levels of IL-6 found in patients with schizophrenia were associated with increased CSF KYNA levels. Administration of IL-6 increased KYNA production in astrocytes and lower GRK3 expression in healthy individuals correlated to increased CSF KYNA levels. GRK3 was further found to be associated with psychosis in patients with bipolar disorder.
Subchronic elevation of KYNA, or lack of GRK3 augmented the amphetamine response as verified by increased locomotor activity and dopamine release. Signs of amplified immune activity were evident in Grk3-/- mice by increases in astrocyte markers, IL-1β, kynurenine, and KYNA turnover. Intracerebroventricular (ICV) administration of IL-1β, and dual, bot not single injections of LPS increased brain KYNA. In addition, mice injected ICV with IL-1β or lacking GRK3 showed disrupted prepulse inhibition (PPI).
Results presented here point to an intimate relationship between immune activation, the kynurenine pathway, and psychosis. Specifically, immune activation, present in patients with schizophrenia, was demonstrated to activate the kynurenine pathway. In addition, activation of the kynurenine pathway induced KYNA and lead to behavioral aberrations in rodents.
The aim of this thesis was to further investigate the role of KYNA in the pathophysiology of schizophrenia. Thus, patients with schizophrenia were examined with respect to cerebrospinal fluid (CSF) levels of interleukin (IL)-6, kynurenines, and the functional effects of G protein- coupled receptor kinase 3 (GRK3) expression. Mice administered lipopolysaccharide (LPS), amphetamine, or lacking the immune-regulating enzyme GRK3, were studied with respect to biochemical and functional aberrations associated with schizophrenia.
The elevated CSF levels of IL-6 found in patients with schizophrenia were associated with increased CSF KYNA levels. Administration of IL-6 increased KYNA production in astrocytes and lower GRK3 expression in healthy individuals correlated to increased CSF KYNA levels. GRK3 was further found to be associated with psychosis in patients with bipolar disorder.
Subchronic elevation of KYNA, or lack of GRK3 augmented the amphetamine response as verified by increased locomotor activity and dopamine release. Signs of amplified immune activity were evident in Grk3-/- mice by increases in astrocyte markers, IL-1β, kynurenine, and KYNA turnover. Intracerebroventricular (ICV) administration of IL-1β, and dual, bot not single injections of LPS increased brain KYNA. In addition, mice injected ICV with IL-1β or lacking GRK3 showed disrupted prepulse inhibition (PPI).
Results presented here point to an intimate relationship between immune activation, the kynurenine pathway, and psychosis. Specifically, immune activation, present in patients with schizophrenia, was demonstrated to activate the kynurenine pathway. In addition, activation of the kynurenine pathway induced KYNA and lead to behavioral aberrations in rodents.
List of papers:
I. Olsson, S. K., Larsson, M. K., Erhardt, S. (2012). Subchronic elevation of brain kynurenic acid augments amphetamine-induced locomotor response in mice. Journal of Neural Transmission. 119(2), 155–163.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Schwieler, L., Larsson, M. K., Skogh, E., Kegel, M. E., Orhan, F., Abdelmoaty, S., et al. (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of Psychiatry & Neuroscience : JPN. 39(6), 140126.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Carl Sellgren, Markus Larsson, Funda Orhan, Magdalena E Kegel, Ida Nilsson, Susan B Powell, S Caldwell, M Kamenski, Sarah E Bergen, Lilly Schwieler, Camilla I Svensson, Paul Lichtenstein, Martin Schalling, Mikael Landén, Göran Engberg, Sophie Erhardt. Targeting of GRK-3 identifies a molecular pathway leading to glial activation in psychotic disorders. [Manuscript]
IV. Larsson, M.K, Faka A, Bhat M, Goiny M, Orhan F, Oliveros A, Ståhl S, Liu XC, Choi DS, Sandberg K, Engberg G, Schwieler L, Erhardt S. (2015) Repeated LPS injections induce disparate changes in the kynurenine pathway versus a single injection - Relevance for animal models of psychiatric disorders. [Manuscript]
I. Olsson, S. K., Larsson, M. K., Erhardt, S. (2012). Subchronic elevation of brain kynurenic acid augments amphetamine-induced locomotor response in mice. Journal of Neural Transmission. 119(2), 155–163.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Schwieler, L., Larsson, M. K., Skogh, E., Kegel, M. E., Orhan, F., Abdelmoaty, S., et al. (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of Psychiatry & Neuroscience : JPN. 39(6), 140126.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Carl Sellgren, Markus Larsson, Funda Orhan, Magdalena E Kegel, Ida Nilsson, Susan B Powell, S Caldwell, M Kamenski, Sarah E Bergen, Lilly Schwieler, Camilla I Svensson, Paul Lichtenstein, Martin Schalling, Mikael Landén, Göran Engberg, Sophie Erhardt. Targeting of GRK-3 identifies a molecular pathway leading to glial activation in psychotic disorders. [Manuscript]
IV. Larsson, M.K, Faka A, Bhat M, Goiny M, Orhan F, Oliveros A, Ståhl S, Liu XC, Choi DS, Sandberg K, Engberg G, Schwieler L, Erhardt S. (2015) Repeated LPS injections induce disparate changes in the kynurenine pathway versus a single injection - Relevance for animal models of psychiatric disorders. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Erhardt, Sophie
Issue date: 2015-05-22
Rights:
Publication year: 2015
ISBN: 978-91-7549-977-2
Statistics
Total Visits
Views | |
---|---|
Bridging ...(legacy) | 444 |
Bridging ... | 187 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Bridging ... | 2 | 2 | 3 | 1 | 1 | 2 | 0 |
File Visits
Views | |
---|---|
Thesis_Markus_Larsson.pdf(legacy) | 940 |
Thesis_Markus_Larsson.pdf | 320 |
kappa2.pdf(legacy) | 1 |
Top country views
Views | |
---|---|
United States | 154 |
Sweden | 137 |
Germany | 51 |
South Korea | 45 |
China | 40 |
France | 15 |
Poland | 12 |
Ireland | 10 |
Taiwan | 10 |
Finland | 8 |
Top cities views
Views | |
---|---|
Ashburn | 43 |
Stockholm | 38 |
Seoul | 37 |
Kiez | 18 |
Beijing | 14 |
Wilmington | 10 |
Kraków | 8 |
Lindesberg | 7 |
Shenzhen | 7 |
Sunnyvale | 7 |