Project 2: Role of the Kynurenine System on Brain Inflammatory Responses in the Offspring of Immune Challenged Rats
Complications due to infections during pregnancy are a significant risk factor for the emergence of schizophrenia in the offspring. Animal models of prenatal immune challenge provide support for the idea that developmental immune abnormalities promote specific vulnerabilities in the disease. Conversion of the amino acid tryptophan to kynurenine and its metabolites (collectively referred to as kynurenines) activated during viral and bacterial infections.
Focusing especially on the neuroactive metabolite kynurenic acid, this project will evaluate the involvement of kynurenines in an established animal model, caused by prenatal exposure to the viral RNA mimetic poly I:C. The central hypothesis posits that activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in the infected mother leads to increased production of kynurenines, including kynurenic acid, in the fetal brain.
In turn, elevated kynurenic acid levels - which are also seen in the brain of persons with schizophrenia - cause microglia to adopt an alternative state known as M2 activation.
We will test the hypothesis that this shift in activation state is maintained throughout development and is exacerbated in response to stress. We propose that these events result in further enhanced formation of kynurenic acid and account for cognitive impairments later in life.