Pathological events during early brain development are believed to hold the key to the emergence of schizophrenia (SZ) in adulthood. Deficits in memory, attention and executive function, i.e. core domains of the psychopathology of SZ, might be causally related to dysfunctional glutamatergic and nicotinergic transmission. Kynurenine acid (KYNA), an astrocytic metabolite of the kynurenine pathway of tryptophan degradation, is an endogenous inhibitor of 7nACh and NMDA receptors in the brain and has been implicated in the pathology of SZ. Studies using cerebrospinal fluid (CSF) or post-mortem brain tissue of patients with SZ suggest that an excess of KYNA might play a causative role in the disease. As an endogenous antagonist at 7nAChRs and NMDARs, which are both critically involved in cognitive functions, increased KYNA levels in the brain might be especially involved in the cognitive deficits that are seen in individuals with SZ. Importantly, a polymorphism in the gene for kynurenine 3-monooxygenase (KMO), an enzyme involved in the regulation of KYNA neosynthesis, has been associated with elevated KYNA levels and increased risk of developing SZ. The connection between KYNA and SZ may have a developmental dimension as several of the risk factors associated with SZ result in increased formation of kynurenine, the direct bioprecursor of KYNA. The proposed project is based on recent studies showing that elevating brain KYNA in the last week of gestation impaires cognitive functions in the adult offspring. In this context, we propose to build on the model by using genetically modified mice, heterozygous for the Kmo gene, and increasing brain KYNA during the last week of embryonic development. Making comparisons to wild-type controls, we will examine the impact of prolonged exposure to kynurenine in a vulnerable animal that has reduced KMO enzymatic activity. The central hypothesis of this proposal is that elevated KYNA during the prenatal development, produced from its bioprecursor kynurenine, influences the development of the brain and, as a result, alters KP dynamics, extracellular glutamate, modulates hippocampal-mediated cognitive behaviors, and interhemispheric transmission in adulthood. It follows, and will be tested here, that inhibition of KYNA synthesis is a valuable therapeutic strategy to combat cognitive deficits in SZ.
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