Project 1

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Project 1: Manipulation of Brain Kynurenic Acid During Early Development: Short- and Long-Term Effects

Research Summary

Deficits in memory, attention and executive function, i.e. core domains of the psychopathology of schizophrenia, are thought to be causally related to dysfunctional glutamatergic and nicotinergic neurotransmission. Kynurenic acid, an astrocyte-derived tryptophan metabolite, is an endogenous antagonist of ?7 nicotinic and NMDA receptors, both of which are critically involved in cognitive functions.

Increased kynurenic acid levels, which are seen in the brain and cerebrospinal fluid of individuals with schizophrenia, may therefore play a role in the cognitive impairments seen in individuals with the disease.

Several of the risk factors associated with schizophrenia, including prenatal stress or infections, lead to an increased formation of kynurenine, the direct bioprecursor of kynurenic acid; and, in animals, elevated kynurenic acid levels in the fetal brain cause cognitive impairments in adulthood.

Studies in this pre-clinical project are therefore designed 1) to investigate the cellular and molecular events that control kynurenic acid formation in utero; and 2) to test the hypothesis that prenatal elevation of kynurenic acid adversely affects pre- and postnatal brain development and, as a result, impairs kynurenine pathway dynamics, extracellular glutamate levels, and cognitive behavior in adulthood.

The planned studies will also evaluate whether timed inhibition of kynurenic acid synthesis is an effective strategy to prevent pathological events in adulthood.