Imbalanced kynurenine pathway in schizophrenia and depression : immunological and genetic aspects

Kynurenic acid (KYNA), an end metabolite of the kynurenine pathway along tryptophan degradation, has gained increasing interest in the pathophysiology of psychiatric disorders. Elevated levels of KYNA have been found in the cerebrospinal fluid (CSF) and in the postmortem brain of patients with schizophrenia and bipolar disorder with psychotic symptoms. In contrast, reduced levels of KYNA are associated with depressive symptoms. Rapidly emerging evidence points to the involvement of brain immune activation in psychiatric disorders and to the kynurenine pathway as a causal link between brain immune activation and psychiatric disorders. The aim of present thesis was to investigate the role of the kynurenine pathway in the pathophysiology of schizophrenia and depression in experimental settings.

The results show that an infection with neurotropic influenza A virus or a transient elevation of brain KYNA levels in neonatal mice enhanced the sensitivity of d-amphetamine-induced increase in locomotor activity in adulthood. Neonatal elevation of KYNA also impaired prepulse inhibition and working memory in adulthood. These long-lasting behavioral alterations suggest that the kynurenine pathway as a causal link between early-life infection and the development of neuropsychiatric disturbances in adulthood. Reduced KYNA levels were detected in the prefrontal cortex, but not in the frontal cortex, hippocampus, striatum or cerebellum, of Flinders Sensitive Line (FSL) rats, an animal model of depression, compared with their controls, the Flinders Resistant Line (FRL) rats. Inhibition of Kynurenine 3-monooxygenase (KMO) shunts the kynurenine pathway towards enhanced synthesis of KYNA. Mice with a targeted deletion of KMO exhibited impairments in contextual memory and social interaction, potentiated horizontal activity following damphetamine-induced increase in locomotor activity as well as increased anxiety-like behaviors. In addition, genome-wide differential gene expression analyses identified alterations regarding schizophrenia- and psychosis-related genes in these mice. Kynurenine aminotransferase (KAT) II is identified as the main enzyme responsible for most of brain KYNA production. Nevertheless, KAT II KO mice receiving kynurenine injection or repeated injections of Lipopolysaccharide (LPS) exhibited increased concentrations of brain KYNA. Taken together, these results give strong experimental support for the connection between immune activation and KYNA in schizophrenia and suggest that low brain KYNA could be of importance for the depressive-like behaviors observed in FSL rats.

List of scientific papers

I. Xicong Liu, Maria Holtze, Susan B. Powell, Niccolò Terrando, Markus K. Larsson, Anna Persson, Sara K. Olsson, Funda Orhan, Magdalena Kegel, Linnea Asp, Michel Goiny, Lilly Schwieler, Göran Engberg, Håkan Karlsson, Sophie Erhardt. Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid. Brain Behavior and Immunity. 2014;36:80–89.
https://doi.org/10.1016/j.bbi.2013.10.010

II. Xicong Liu, Sophie Erhardt, Michel Goiny, Göran Engberg, Aleksander A. Mathé. Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression. Acta Neuropsychiatrica 2016;13:1-5.
https://doi.org/10.1017/neu.2016.31

III. Sophie Erhardt, Ana Pocivavsek, Mariaelena Repici, Xicong Liu, Sophie Imbeault, Daniel C Maddison, Marian AR Thomas, Joshua L Smalley,Markus K Larsson, Paul J Muchowski, Flaviano Giorgini, Robert Schwarcz. Adaptive changes and behavioral abnormalities in mice deficient in kynurenine 3-monooxygenase: Relevance to psychotic disorders. [Manuscript]

IV. Xicong Liu, Anthi Faka, Lilly Schwieler, Sophie Erhardt. Repeated administration of LPS induces changes in the kynurenine pathway in KAT II deficient mice. [Manuscript]