| Maternal infections during pregnancy are thought to be an important environmental risk factor for psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. It has been suggested that the mother's immune response may be affecting the offspring's neurodevelopment and later behavior. In this thesis, we aimed to develop animal models to study the effects of maternal immune activation (MIA) on offspring behavior. In a first experiment, pregnant rats were injected with bacterial endotoxin (lipopolysaccharide, LPS) on gestational day (E) 18 and 19. The exposed offspring displayed increased amphetamine-induced locomotion, a behavioral indicator of mesolimbic dopamine activity. In a second experiment, LPS was administered in a chronic manner by using osmotic pumps from E18 to birth. Adult offspring displayed decreased prepulse inhibition (PPI), indicating disrupted sensorimotor gating. Prior to studying the effects of MIA elicited by the viral mimic polyinosinic:polycytidylic acid (poly I:C), we characterized the immune reaction it triggered in adult male rats. We demonstrated that poly I:C injection induced a robust febrile response, decreased food intake and body weight, and increased pro-inflammatory cytokines in the circulation. In another study, we compared the disruptive effects of MIA induced by the immunogens poly I:C or LPS to that induced by local inflammation, elicited by intramuscular injection of turpentine. In the same study, we also investigated the existence of gestational windows of susceptibility to the disruptive effects of MIA on offspring PPI. MIA induced by LPS or turpentine significantly decreased offspring PPI only when administered at certain times during gestation. Poly I:C had no effect at the dose administered. Thus our results demonstrated that selection of the immune agent and gestational time of administration are both critical factors in MIA models. Finally, we investigated if gestational MIA affected offspring immune function. Our results indicated no change in pyrogenic and cytokine responses to an immune challenge in adult MIA-exposed rats.;In conclusion, the work in this thesis provides evidence that gestational MIA can cause lasting alterations in offspring behavior. This lends support to the idea that the association between prenatal infection and increased schizophrenia in human epidemiological studies reflects a causal relationship. |
