Investigation of the effects of IL-17a cytokine on human neural cells and on autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disease characterized by deficits in social communication and interaction, as well as by repetitive and stereotyped behaviors. In most cases, the cause of ASD is not completely understood, but it is commonly associated with heterogeneous genetic and environmental backgrounds. Among the most important environmental risk factors for ASD, Maternal Immune Activation (MIA) via infection during pregnancy has been reported as a risk factor for ASD in the offspring. In addition, it has been suggested that MIA may act in concert with ASD susceptibility genes to increase risk for ASD. Recent studies using animal models suggest that the maternal interleukin-17a (IL-17a) plays a key role in MIA-induced alterations in the cortex cytoarchitecture and ASD-associated behavioral abnormalities in offspring. However, the cellular and molecular mechanisms by which IL-17a acts to cause these phenotypes are still poorly understood. This study aims to verify whether IL-17a acts on the proliferation and differentiation of human neural cells, to characterize the intracellular signaling pathways induced by IL-17a that mediate these cellular phenotypes, and to explore whether IL-17a and ASD susceptibility genes synergize to "amplify" changes in human neural cells. To achieve these objectives, we will use as experimental model neuroprogenitor cells derived from induced pluripotent stem cells (iPSCs) of ASD patients and control individuals, which will be treated with vehicle or IL-17a in different concentrations and time points. We will perform proliferation and differentiation assays (differentiation into neurons, oligodendrocytes and astrocytes), we will analyze mRNA and protein expression of known IL-17a downstream signaling components, as well as of mTORC1 pathway components, whose deregulation has been linked to both MIA and ASD. (AU)