Bridging immune activation with the kynurenine pathway : implications for psychosis

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.

List of scientific 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.
https://doi.org/10.1007/s00702-011-0706-6

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.
https://doi.org/10.1503/jpn.140126

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]