Brain immune mechanisms in schizophrenia : experimental and clinical characterization

The role of inflammation has become increasingly evident in the pathophysiology of schizophrenia and thought to one of the major causes of the symptoms. Interestingly, immune activation has been linked to the kynurenine pathway of tryptophan degradation, which produces an array of neuroactive metabolites. Most notably, the end-metabolite kynurenic acid (KYNA) has been described as an endogenous antagonist on the obligatory glycine-site of the N-methyl-D-aspartate (NMDA) receptor. In similarity to other NMDA receptor antagonists, KYNA has been shown to produce symptoms similar to those seen in schizophrenia. Accordingly, elevated levels of KYNA has been found in the cerebrospinal fluid (CSF) and post-mortem brains of patients with schizophrenia, along with an elevation of pro-inflammatory cytokines.

The identification of elevated brain KYNA as a potential cause for the symptoms in schizophrenia offers exciting opportunities for new treatment options for schizophrenia. In the present thesis, we show that a specific inhibitor of KAT II, the primary enzyme responsible for the production of KYNA, causes a robust decrease in ventral tegmental area dopamine cell activity, suggesting beneficial effects of the inhibitor for psychosis. However, in order to properly evaluate novel antipsychotic drugs explicitly targeting the kynurenine pathway, proper modeling has to be considered.

This thesis aimed to provide a platform where such drugs can be tested appropriately. Thus, in the present thesis, we characterize different ways of modeling elevated KYNA in rodents, anchored to clinical findings, with regards to behavioral aspects relevant to schizophrenia and dopamine activity. We highlight the importance of proper modeling in KMO K/O mice, where we saw different effects of established antipsychotics and drugs that were previously shown to lower KYNA based on endogenous KYNA levels. Additionally, we characterize different processes involved in the pathophysiology of schizophrenia using CSF and serum of a small first-episode psychosis cohort. Our analysis provides an unbiased confirmation for the involvement of inflammation and the kynurenine pathway in schizophrenia through metabolomics.

List of scientific papers

I. Klas Linderholm*, Maximilian Tufvesson Alm*, Markus Larsson, Sara Olsson, Michel Goiny, Mihaly Hajos, Sophie Erhardt, Göran Engberg. Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons. Neuropharmacology. 2016 Mar;102:42-7. *Both authors contributed equally.
https://doi.org/10.1016/j.neuropharm.2015.10.028

II. Maximilian Tufvesson-Alm, Lilly Schwieler, Robert Schwarcz, Michel Goiny, Sophie Erhardt, Göran Engberg. Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia. Neuropharmacology. 2018 Aug;138:130-139.
https://doi.org/10.1016/j.neuropharm.2018.06.003

III. Maximilian Tufvesson-Alm, Sophie Imbeault, Xicong Liu, Lilly Schwieler, Göran Engberg, Sophie Erhardt. Dual administration of LPS causes behavioral disturbances associated with the psychopathology of schizophrenia. [Manuscript]

IV. Carl Sellgren*, Sophie Imbeault*, Markus Larsson, Alfredo Oliveros, Ida Nilsson, Jessica Gracias, Simone Codeluppi, Maria Bhat, Maximilian Tufvesson-Alm, Funda Orhan, Magdalena Kegel, Anthi Faka, Marie Svedberg, Susan Powell, S. Caldwell, M. Kamenski, Michel Goiny, Camilla Svensson, Martin Schalling, Tomas Hökfelt, Lilly Schwieler, Simon Cervenka, Doo-Sup Choi, Mikael Landén, Göran Engberg, Sophie Erhardt. Functional aspects of GRK3 in brain immune activation and psychosis. *Both authors contributed equally. [Manuscript]

V. Daniel Lindberg, Maximilian Tufvesson-Alm, Funda Orhan, Surendra Dasari, Lee Peyton, Fredrik Piehl, Karolinska Schizophrenia Project (KaSP) Consortium, Simon Cervenka, Sophie Erhardt, Doo-Sup Choi. Identification of metabolomic biomarkers associated with first-episode psychosis and antipsychotic treatment within the cerebrospinal fluid and serum. [Manuscript]