Doctor of Philosophy
Maternal infection during the first or second trimester of pregnancy poses a risk factor for the child to have neurodevelopmental disorders like autism spectrum disorder (ASD) and schizophrenia. Various clinical and preclinical studies have shown that the maternal immune response to infection, also known as maternal immune activation (MIA), can disrupt fetal brain development.
Over the past two decades, MIA has been studied in rodents using the Polyinosinic Polycytidylic acid (Poly I:C) rodent model. Poly I:C has a molecular pattern resembling viruses that can induce a robust immune response. Following exposure to Poly I:C MIA, rodent offspring exhibit many brain and behavioural symptoms related to ASD and schizophrenia.
Despite the well-established validity of the Poly I:C model, there are knowledge gaps that require further investigation to obtain a comprehensive understanding of the effects of MIA on brain development. Firstly, few studies have directly compared the effects of administering Poly I:C MIA at different times during gestation. Secondly, the role of many molecular and cellular components of the maternal immune response to Poly I:C remain unknown. Thirdly, few studies have attempted to study how Poly I:C MIA interacts with other neurodevelopmental risk factors such as genetic mutations.
In this thesis, my work shows that Poly I:C MIA is more detrimental in early gestation compared to late gestation with regards to altering offspring sensory processing phenotypes measured through the acoustic startle response. Using a genetic knockout model, my experiments also showed that Interleukin (IL)-15, a cytokine that is involved in the antiviral immune response, modulates the effects of early gestation Poly I:C MIA. Lastly, I found that Poly I:C MIA interacts with a genetic deficiency in the ASD risk gene CNTNAP2 to exacerbate sensory processing disruptions in the offspring.
Together, the findings from this thesis provide a detailed assessment of sensory processing in the Poly I:C MIA model and offer insight into its potential underlying mechanisms.
Summary for Lay Audience
The human brain is a complex organ that develops over decades, from its time in the womb until early adulthood. During pregnancy, many highly specific foundational processes must take place to transform the fetal brain from a tiny ball of cells to a complex organ with a variety of structures and functions.
Throughout its elaborate journey, the fetal brain is susceptible to bumps in the road, often related to the maternal environment. Some of these bumps are widely known and include smoking and alcohol consumption during pregnancy. Others like maternal infection during pregnancy are known but not well understood.
Human studies have shown that maternal infection during pregnancy increases a child’s risk to later develop autism spectrum disorder or schizophrenia. This risk is highest if the infection is severe and occurs in the first half of pregnancy. Moreover, the risk exists regardless of infection type. Be it a bacterial infection like salmonella or a viral infection like COVID-19, all infections activate the maternal immune response, which is thought to be the culprit.
Research in animal models has supported the maternal immune activation (MIA) hypothesis. We know that MIA during pregnancy in rodents can alter the structure of the offspring’s brain as well as their behaviour. However, there are still many unknowns, some of which were the focus of my thesis. First, it is still unclear how MIA at different times during pregnancy impacts the brain differently. In addition, the maternal immune response has many molecular components, but the role of many of them remains unknown. Finally, it is unclear if other risk factors like genetic mutations can increase the susceptibility to MIA and worsen symptoms related to autism or schizophrenia.
My thesis investigates these 3 questions in greater detail in a rat model. My findings support the conclusion that earlier MIA leads to worse outcomes. Additionally, the results identify Interleukin-15 as a molecule that could mediate some of MIA’s effects and suggest that those with a genetic mutation related to autism may be more susceptible to the effects of MIA during pregnancy.
Haddad, Faraj, "Investigating the effects of maternal immune activation on sensory processing: Timing, immune mechanisms, and gene-environment interactions" (2021). Electronic Thesis and Dissertation Repository. 8103.
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