Maternal Immune Activation and Abnormal Behavior in the Adult Offspring: Towards a Mechanism

Citation

Smith, Stephen Edward Paucha (2008) Maternal Immune Activation and Abnormal Behavior in the Adult Offspring: Towards a Mechanism. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/CB5Y-P545. https://resolver.caltech.edu/CaltechETD:etd-05132008-133518

Abstract

Maternal infection is a risk factor for both schizophrenia and autism. The offspring of women who develop an infection during pregnancy are several times more likely to develop these diseases compared to offspring from uncomplicated pregnancies. Modeling this risk factor in animals, when pregnant rodents are given an influenza infection during pregnancy, their offspring show several behavioral and histological abnormalities consistent with human mental illness. Maternal injection of non-infectious, immune-activating compounds, such as the dsRNA poly(I:C), yields similar results, suggesting that the maternal immune response causes deleterious changes in fetal brain development. The main focus of this thesis is establishing the importance of a single component of the maternal immune response, the cytokine interleukin-6 (IL-6), in mediating the observed changes in the brain development and behavior of the offspring. In addition, I report new observations on the offspring of poly(I:C)-activated pregnant mice that are consistent with findings in autism and schizophrenia: a localized deficit of Purkinje cells in the cerebellum, abnormal eye-blink conditioning, abnormal hippocampal-dependent behaviors and hyper-sensitivity to dopamine in the hippocampus. I also present data on the immune reaction to poly(I:C) in pregnant non-human primates. Finally, I describe preliminary findings on the identification of factors that act down-stream of IL-6. The mechanism through which maternal immune activation causes abnormal behavior in the offspring could illuminate important pathways that contribute to the pathogenesis of schizophrenia and autism.

Thesis Files