Several lines of evidence link the endogenous neuromodulator kynurenic acid (KYNA), a major metabolite of the essential amino acid tryptophan and antagonist of both a7 nicotinic and N-methyl-D-aspartate (NMDA) receptors, causally to the cognitive deficits seen in individuals with schizophrenia (SZ): 1) brain and cerebrospinal fluid KYNA levels are increased in SZ;2) a7 nicotinic and NMDA receptors play critical roles in both neurodevelopment and cognition;3) in animals, perinatal increases in brain KYNA cause an array of SZ-like abnormalities and vulnerabilities in adulthood;4) experimental KYNA elevations cause cognitive dysfunctions reminiscent of SZ;5) brain KYNA metabolism is stimulated by stress and immune stimulation during early development;and 6) first results indicate that inhibitors of KYNA biosynthesis ("KAT II inhibitors") show efficacy in animal preparations that are believed to be informative for SZ pathophysiology. The proposed Center is based on three premises: 1) SZ is a complex psychiatric illness in which stress/immune challenges during pregnancy set the stage for the emergence of the disease in vulnerable offspring;2) Stressful events during development precipitate the early presentation of cognitive impairments in susceptible individuals by disproportionally elevating brain KYNA levels;and 3) Pharmacological reduction of brain KYNA synthesis offers a promising new therapeutic target in SZ, especially for pro-cognitive interventions. Hypotheses derived from these insights and from supportive preliminary results in animals and humans will be tested in two pre-clinical and two clinical projects. All studies will be led by established and highly interactive laboratory-based and clinical faculty, and the host institution has the appropriate infrastructure to embark on this overarching and highly synergistic translational project. Notably, the planned research strategy fits the Strategic Plan of the NIMH, which calls for a) discoveries of the causes of mental disorders, b) charting of disease trajectories to optimize treatment, and c) the development of new and better therapeutic interventions.
Deficits in cognitive functions are a core symptom of pathology in schizophrenia, a debilitating disorder affecting ~ 1 % of the world population. The proposed Center, organized in four highly complementary and synergistic projects in animals and humans, is designed to provide new insights into the role of the tryptophan metabolite kynurenic acid (KYNA) in cognition, and to examine inhibition of KYNA formation as a novel strategy to overcome cognitive impairments.
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