One in 68 children are diagnosed with autism spectrum disorders (ASD) in the US, yet there are currently no fundamental therapies available. Furthermore, epidemiological research suggests that nearly five times more boys than girls are affected by ASD, but the mechanisms behind this sex dimorphism are not well understood. It is known that both genetic and environmental factors are involved in ASD pathogenesis. Of the environmental factors, epidemiology suggests that prenatal inflammation induced by maternal infection is associated with an increased risk of ASD, yet the mechanisms behind this link still need to be elucidated. Our lab has been working on understanding how environmental factors affect normal brain development and functions by focusing on how microglia, resident immune cells in the central nervous system, control innate immune responses in the brain. More specifically, we are interested in whether sex hormones and their corresponding nuclear receptors (Estrogen Receptors and Androgen Receptor) may be able to induce changes in gene expression and epigenetic regulation in microglia that can restore normal CNS functions and improve neuroinflammatory diseases such as ASD. Our central hypothesis for this proposal is that innate immune signaling, such as toll-like receptor (TLR)-mediated inflammation in fetal microglia, is involved in inducing specific, ASD-like behavior changes. Furthermore, we predict that the expression levels of anti-inflammatory ER? ligands in fetal microglia determine their sensitivity to prenatal inflammation and contribute to the male bias observed in ASD. We will test these hypotheses using mouse models of prenatal inflammation-induced ASD. The primary goal of this proposal is to understand how differential responses to TLR-mediated prenatal inflammation can affect long-term fetal microglial transcription and epigenetic regulation, resulting in ASD-like behaviors. Moreover, we will determine whether modulation of ER?-mediated transcription and epigenetic regulation can restore normal microglial functions affected by prenatal inflammation, thus ameliorating ASD- like behaviors in offspring. The expected overall impact of this proposal is that it will expand the mechanistic understanding of distinct maternal and fetal TLR-mediated signaling pathways by clarifying how they are associated to specific behavior changes observed in ASD. We will also fully elucidate how ERs and their ligands contribute to the male bias observed in ASD and how these ligands can restore homeostasis in microglia to improve ASD-like behaviors in a mouse model.
Infection during pregnancy and being male are known to be associated with increased risks of autism, but the causative mechanisms are not well understood. In this proposal, we focus on understanding how microglial cells, resident immune cells in the brain, can be differentially regulated by sex hormone nuclear receptors and their ligands in their responses to prenatal inflammation. Overall, our goal is to develop new therapeutic strategies using sex hormones to control inflammation in fetal microglia, thus treating and/or preventing the development of autism spectrum disorders.
