Complications due to infections during pregnancy are a significant risk factor for the emergence of schizophrenia (SZ) in the offspring. Animal models of prenatal immune challenge provide support for the idea that developmental immune abnormalities promote specific vulnerabilities of the disease. Conversion of the amino acid tryptophan to kynurenine (KYN) and its associated metabolites (collectively referred to as kynurenines) is one ofthe mechanisms activated during viral and bacterial infections. In particular, kynurenic acid (KYNA) is known to have neuroactive properties and is also elevated in the cerebral cortex of SZ patients. The purpose ofthe present project is to evaluate the involvement ofthe kynurenine system in the established animal model of prenatal infection. The central hypothesis is that activation ofthe enzyme indoleamine 2,3-dioxygenase (IDO) in response to the viral RNA mimetic poly l:C in the mother leads to increased production of kynurenines, including KYNA in the brain of embryos. This increase in KYNA will in turn be responsible for promoting microglia to adopt an alternative activated state also known as M2 activation. It is further hypothesized that this shift in activation state will be maintained throughout development, at least in a proportion of microglia, and that it will be exacerbated in response to stressors resulting in enhanced production of KYNA in the brain. In concert with the central hypothesis ofthe center grant, an increase in KYNA levels in the brain is believed to be responsible for cognitive impairments. We will test these hypotheses using rats prenatally challenged with poly l:C and subjected to a series of studies including a) documenting the trajectory of changes in the kynurenine pathway during pre and post- natal brain development and in relation to microglia activation;b) evaluating peripheral and central kynurenines and microglial responses to social stressors during peri-adolescence;and c) testing whether timed KAT II inhibition (reduction of KYNA production) prevents and/or reverses the neurobehavioral deficits seen in peri- adolescents. The present project will also involve the study of peripheral and placental cytokine and kynurenine responses in the mothers, as well as peripheral and central immune responses in the offspring.

Public Health Relevance

Research has shown that maternal infections during pregnancy are an important risk factor for schizophrenia in the offspring. The aim of this project is to determine the role of the kynurenine system in this process;this system is known to participate in immune responses and provides modulatory function for nerve cells. These studies will employ pregnant rats treated with viral agents and will analyze the brain kynurenine and immune responses of the offspring at different developmental stages and cognitive performance in behavioral tests.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
United States
Zip Code
Rowland, Laura M; Summerfelt, Ann; Wijtenburg, S Andrea et al. (2016) Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia. JAMA Psychiatry 73:166-74
Wang, Qi; Chen, Rong; JaJa, Joseph et al. (2016) Connectivity-Based Brain Parcellation: A Connectivity-Based Atlas for Schizophrenia Research. Neuroinformatics 14:83-97
Pershing, Michelle L; Phenis, David; Valentini, Valentina et al. (2016) Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding. Psychopharmacology (Berl) 233:3725-3735
Chiappelli, Joshua; Shi, Qiaoyun; Kodi, Priyadurga et al. (2016) Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia. Psychoneuroendocrinology 63:86-93
Kochunov, Peter; Ganjgahi, Habib; Winkler, Anderson et al. (2016) Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia. Hum Brain Mapp 37:4673-4688
Du, Xiaoming; Kochunov, Peter; Summerfelt, Ann et al. (2016) The role of white matter microstructure in inhibitory deficits in patients with schizophrenia. Brain Stimul :
Rowland, L M; Krause, B W; Wijtenburg, S A et al. (2016) Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. Mol Psychiatry 21:198-204
Kochunov, Peter; Thompson, Paul M; Winkler, Anderson et al. (2016) The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects. Neuroimage 125:189-97
Keefe, Richard S E; Haig, George M; Marder, Stephen R et al. (2016) Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia. Schizophr Bull 42:19-33
Kochunov, Peter; Rowland, Laura M; Fieremans, Els et al. (2016) Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia. Proc Natl Acad Sci U S A 113:13504-13509

Showing the most recent 10 out of 35 publications