Several lines of evidence link the endogenous neuromodulator kynurenic acid, a major metabolite of the essential amino acid tryptophan, causally to the cognitive deficits seen in individuals with schizophrenia:
- alpha-7 nicotinic and NMDA receptors, the primary targets of kynurenic acid in the brain, play critical roles in both neurodevelopment and cognition
- Brain and cerebrospinal fluid kynurenic acid levels are increased in people with schizophrenia
- In animals, brain kynurenic acid production during early brain development is stimulated by stress and immune system activation, two risk factors of schizophrenia
- Prenatal and/or early postnatal increases in brain kynurenic acid levels in animals cause an array of schizophrenia-like abnormalities and vulnerabilities in adolescence and adulthood
- Inhibitors of kynurenic acid biosynthesis (“KAT II inhibitors”) show efficacy in animal preparations that are informative for schizophrenia
Conceptually, the Center is based on three premises:
- Schizophrenia is a complex psychiatric illness in which stress/immune challenges during pregnancy set the stage for the emergence of the disease in vulnerable offspring
- Stressful events/immunological abnormalities during pregnancy precipitate the presentation of cognitive impairments in susceptible individuals by elevating brain kynurenic acid levels both in utero and in adulthood
- Pharmacological reduction of brain kynurenic acid synthesis offers a promising new approach for pro-cognitive interventions in schizophrenia
Principal Investigator: Robert Schwarcz, PhD
Examination of the molecular and cellular mechanisms that normally regulate kynurenic acid production in the animal brain during prenatal development, and exploration of the long-term effects of increased fetal kynurenic acid formation.
Dr. Alexandre Bonnin serves as Co-Investigator on this project.
Principal Investigator: Leonardo H. Tonelli, PhD
Investigation of the acute and chronic impact of prenatal stress and immune challenges on kyrnurenic acid levels and function in animals. Evaluation of the effects of an additional second surge of kynurenic acid in adolescence ("double-hit" hypothesis).
Principal Investigator: L. Elliot Hong, MD
Study of the effects of psychological and other stressors on kynurenic acid metabolism in healthy human subjects and in individuals with schizophrenia, using an array of state-of-the art imaging, electrophysiology and modeling approaches.
Dr. Peter Kochunov, Dr. Laura M. Rowland, and Dr. Malle A. Tagamets serve as Co-Investigators on this project.
Principal Investigator: Robert W. Buchanan, MD
Examination of the effects of an acute tryptophan challenge in healthy controls and in people with schizophrenia on neural circuit and cognitive performance using functional and chemical neuroimaging measures, neuropsychological assessments and peripheral endocrine and immune markers.
Dr. James M. Gold, Dr. Deanna L. Kelly, Dr. Laura M. Rowland and Dr. Peter Kochunov serve as Co-Investigators on this project.