Investigating the effects of maternal immune activation on sensory processing: Timing, immune mechanisms, and gene-environment interactions
Abstract
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.