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|Title:||Adaptive and Behavioral Changes in Kynurenine 3-monooxygenase Knockout Mice: Relevance to Psychotic Disorders|
Maddison, Daniel C.
Thomas, M. A. R.
Smalley, Joshua L.
Larsson, M. K.
Muchowski, P. J.
|Publisher:||Elsevier for Society of Biological Psychiatry|
|Citation:||Biological Psychiatry, 2016|
|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.|
|Embargo on file until:||12-Dec-2017|
|Rights:||Creative Commons “Attribution Non-Commercial No Derivatives” licence CC BY-NC-ND, further details of which can be found via the following link: http://creativecommons.org/licenses/by-nc-nd/4.0/ Archived with reference to SHERPA/RoMEO and publisher website.|
|Appears in Collections:||Published Articles, Dept. of Genetics|
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|Erhardt et al. Biological Psychiatry accepted version.pdf||Post-review (final submitted author manuscript)||2.31 MB||Adobe PDF||View/Open|
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