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theses

Stimulation of the immune system during pregnancy, known as maternal immune activation (MIA), can cause long-lasting neurobiological and behavioral changes in the offspring. This phenomenon has been implicated in the etiology of developmental psychiatric disorders, such as autism and schizophrenia. Much of this evidence is predicated on animal models that rely on activation of the innate immune system using bacterial agents such as LPS and/or viral mimics such Poly I:C, both of which act through toll-like receptors. Fewer studies have examined the role of direct activation of maternal T-cells during pregnancy and whether this also results in altered neurobiological and behavioral outcomes in offspring. Bacterial ‘superantigens’, such as Staphylococcal Enterotoxin A and B (SEA; SEB), are microbial proteins that activate CD4+ T-cells and cause prominent T-cell proliferation and cytokine production. We injected pregnant and non-pregnant adult female C57BL/6 and Balb/c mice with 5μg of SEA, SEB, or 0.9% saline, and measured splenic T-cell-derived cytokine concentrations (viz., IL-2, IFN-γ, IL-6, and IL-4) 2 hours later; animals injected with SEA were also measured for splenic concentrations of TNF-α and IL-17A. Half of the injected pregnant animals were brought to term, and their offspring were tested on a series of cognitive tasks starting at six weeks of age (postnatal day 42 [P42]). These tasks included a social interaction task, the elevated plus maze (EPM), an object recognition (OR) task, prepulse inhibition (PPI) of sensorimotor gating, and the Morris water maze (MWM). Results showed that SEA and SEB induced significant concentrations of all measured cytokines, and in particular IFN-γ, in both strains of pregnant mice when compared to controls. While C57BL/6 animals responded with significantly greater concentrations of most proinflammatory cytokines to SEA exposure, Balb/c mice had greater cytokine concentrations to SEB exposure. In addition, pregnant animals exhibited reduced production of proinflammatory cytokines, and in the case of Balb/c SEB-injected mice, increased anti-inflammatory cytokine IL-4. Behavioral results showed distinct phenotypes among offspring from SEA- or SEB-injected mothers. C57BL/6 offspring from SEA-injected mothers displayed decreases in social behavior and spatial learning, and increases in anxiety, locomotion, interest in a novel object, short-term spatial memory, and depressive-like behaviors. Balb/c offspring from SEB-injected mothers displayed decreases in spatial learning, and increases in social behavior, anxiety, sensorimotor gating abilities, and depressive like-behaviors. Overall, through the novel use of SEA and SEB as prenatal immune challenges, we were able to elicit significant cytokine production in the mothers and distinct behavioral profiles in the offspring that both mirrors and diverges from previous models of maternal immune activation in important ways. We conclude that T-cell-mediated maternal immune activation is a valid and valuable model for studying the effects of prenatal immune challenge on neurodevelopmental and behavioral alterations in offspring relevant to psychological diseases.

ETD_8257

Ph.D.

Includes bibliographical references

by Ruth M. Glass

doi:10.7282/T3TH8QVN

ETD doctoral

The author owns the copyright to this work.