Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

Abstract

BACKGROUND Kynurenine 3-monooxygenase (KMO) converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway - which is implicated as dysfunctional in various psychiatric disorders - towards enhanced synthesis of kynurenic acid (KYNA), an antagonist of both α7 nicotinic acetylcholine and NMDA receptors. Possibly as a result of reduced KMO activity, elevated central nervous system levels of KYNA have been found in patients with psychotic disorders, including schizophrenia (SZ). METHODS In the present study, we investigated adaptive – and possibly regulatory – changes in mice with a targeted deletion of Kmo (Kmo−/−) and characterized the KMO-deficient mice using six behavioral assays relevant for the study of SZ. RESULTS Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of SZ- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. KYNA levels were also increased in these brain regions in Kmo−/− mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo−/− mice exhibited impairments in contextual memory and spent less time than controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light-dark box. After a D-amphetamine challenge (5 mg/kg, i.p.), Kmo−/− mice showed potentiated horizontal activity in the open field paradigm. CONCLUSIONS Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.

LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning

“…Remarkably, pharmacological inhibition of KMO in conjunction with L-Kynurenine administration confirmed these observations as we detected a significant dampening of CaMKII phosphorylation in the mPFC and vHip. Since KMO inhibition is known to increase KYNA (Justinova et al, 2013; Moroni et al, 2005), our results supports the hypothesis that excess levels of KYNA possibly contributes to exacerbations in cognitive malfunction (Erhardt et al, 2016; Heisler and O'Connor, 2015). Furthermore, our novel findings promote the possibility that LPS-driven neuroinflammatory signaling contributes to deficits in stimulus processing preferentially through the mPFC.…”

“…Moreover, our study is the first to show that pharmacological inhibition of KMO, which deviates kynurenine conversion toward KYNA (Erhardt et al, 2004; Justinova et al, 2013; Speciale et al, 1996), can effectively increase PKC-Nrgn phosphorylation in the mPFC. Supporting our findings, KMO null mice, which exhibit increased brain KYNA, also upregulates Nrgn mRNA expression (Erhardt et al, 2016). As with LPS administration, no significant changes to Nrgn signaling was detected in the vHip from KMO inhibition.…”

WITHDRAWN: The secret behind peripheral inflammation and depression: The hypothalamus

“…Models that support the in uence of the HPA axis on depression postulate chronically dysregulated activation of the HPA axis, which is also associated with dysregulation of immune function [8][9][10][11] . Various animal studies have shown the relationship between depression and in ammation [12][13][14][15] . In a human study, Pedraz-Petrozzi recently showed correlations between the severity of depression, assessed with the BDI-FS 16 , and the pro-in ammatory cytokine TNF-α in people with depression.…”

Maternal genotype determines kynurenic acid levels in the fetal brain: Implications for the pathophysiology of schizophrenia

“…Thus, systemic administration of a selective KMO inhibitor to the dam during the final prenatal week results in distinct structural and behavioral impairments in the offspring in adolescence and adulthood (Forrest et al, 2013a;Forrest et al, 2013b;Khalil et al, 2014;Pisar et al, 2014), supporting the potential relevance of prenatal KYNA elevations for the emergence of SZ pathology later in life. Notably, we recently found similar biochemical and behavioral abnormalities reminiscent of SZ in adult mice with a complete deletion of the Kmo gene (Kmo -/mice; Erhardt et al, 2017).…”