Pathological events during eariy 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 ofthe kynurenine pathway of tryptophan degradation, is an endogenous inhibitor of a7nACh 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 a7nAChRs 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. The connection between KYNA and SZ may have a developmental dimension as several ofthe risk factors associated with SZ, including prenatal infections, result in the activation of a cytokine-responsive enzyme that catalyzes an increase in the formation of kynurenine, the direct bioprecursor of KYNA. The proposed project is based on recent studies showing that elevating brain KYNA from embryonic day (ED) 15 to postnatal day (PD) 21 results in impaired cognitive function in the adult offspring. The planned experiments are centered around the fundamentally new concept, supported by preliminary data included in this proposal, that elevating KYNA during the prenatal developmental period alone may serve as a model to study the etiology of cognitive dysfunction in SZ. The central hypothesis of this proposal is that elevated KYNA formation during prenatal development, produced from its bioprecursor kynurenine, influences the development ofthe brain and, as a result, alters kynurenine pathway dynamics, extracellular glutamate levels, and modulates hippocampal-mediated cognitive behavior 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.

Public Health Relevance

Cognitive dysfunctions are a core domain of the psychopathology of schizophrenia (SZ), a debilitating disorder affecting ~ 1 % ofthe population. The proposed work is designed to provide new insights into the role of kynurenic acid (KYNA), a neuroactive compound that is elevated in the brain of individuals with SZ, in cognition, and examine inhibition of KYNA formation as a novel strategy to overcome cognitive dysfunction.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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University of Maryland Baltimore
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