Role of IL-17A in maternal inflammation-mediated autism spectrum disorder

Background and challenge Autism spectrum disorder (ASD) impacts more than 28 million individuals worldwide, with approximately 700,000 people affected in the UK. The economic impact on the UK is significant, exceeding £27 billion annually. Numerous epidemiological studies consistently link maternal immune activation (MIA) resulting from infections, autoimmune conditions, or genetic predispositions during pregnancy to an increased risk of neurodevelopmental disorders, including ASD, in offspring. Understanding the impact of MIA on foetal brain development is crucial, especially considering the heightened risk associated with SARS-CoV-2 infection during pregnancy amid the COVID-19 pandemic. Research using animal models to mimic conditions similar to those seen in MIA has highlighted its connection to the development of ASD. These studies showed changes in behaviour and brain structure like what is observed in ASD. However, we still don't fully understand the specific ways this happens at the cellular and molecular levels. It's crucial to recognize that while animal models give us helpful information, they have some limitations in completely mirroring human brain development because of differences between species. Therefore, a human-specific model system is essential to study how MIA contributes to the onset of ASD more accurately. How do we overcome the challenge? To address this limitation and knowledge gap, we've created a novel model system called "cerebroids," a unique 3D culture of human foetal brain tissue with which we can study brain development. This innovative approach allows us to closely examine brain development by accurately representing diverse cell types and developmental stages within the foetal brain. Using this model, we aim to uncover why there is an increased risk of autism when mothers experience immune activation during pregnancy. Questions we will ask during this project? Cytokines are small molecules released by immune and blood cells to coordinate the immune response and trigger reactions in other cells. One specific cytokine, IL-17A, increases in concentration when a pregnant mother experiences an infection. It reaches the baby's brain during pregnancy and plays a crucial role in how the immune system responds in the fetal brain during MIA. However, the exact effects of higher IL-17A levels on the developing brain are not fully understood. This research proposal aims to determine the impact of increased IL-17A levels on key cell types in the developing cortex, including neural stem cells, neurons, and microglia. We will address specific questions to uncover more about this process. How does IL-17A influence the creation of new neurons in the developing brain? How does IL-17A affect the development of brain cells and their organization into layers? How do the brain's immune cells react to elevated levels of IL-17A, and how does this impact their communication with other cells? What do we hope to achieve overall? By using a special 3D model that mimics the development of the human foetal brain, we aim to understand how a key immune molecule called IL-17A affects certain cellular processes and molecular pathways during MIA. The ultimate aim is to uncover more about how ASD develops and find new targets that could be important for early diagnosis and the development of interventions and treatments.