Environmental and genetic risk factors in Autism Spectrum Disorder: a stereological study
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Autism spectrum disorders (ASD), include a group of heterogeneous neurodevelopmental disorders (NDDs) characterized by impaired social interaction, and communication with restricted patterns of behaviour. The aetiology of ASD is very complex and is mainly characterized by the combination of environmental and genetic risk factors, which generate a variable range of different phenotypes. This thesis investigated two of the main environmental risk factors majorly involved in fetal development: hypoxia and inflammation, to conclude with the investigation of the genetic component to the disorder using stem cell technologies. The intrauterine environment plays a key role in normal neural development. The use of an animal model of chronic fetal hypoxia, revealed a series of morphological alterations of the placenta and its compartments, mainly characterised by impaired vascularization, and consequent reduction of the blood flow to the utero-placental circulation. The successive investigation of the brain morphology in the offspring, showed no significant differences in brain size and neocortical thickness, however the stereological analysis revealed a significant increase of the neuronal nuclear volume associated with the reduced numerical density (Nv) of cortical cells. The second series of studies investigated the involvement of the inflammatory component through the use of the most common pro-inflammatory cytokines: tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β and IL-6, whose relevance is due by their ability to cross the placenta and to affect fetal brain development. Results showed a significant reduction of neurite length in SH-SY5Y treated cells with the three cytokines, and impaired neurite outgrowth and viability in E14 dopaminergic (DAergic) neurons treated with TNF-α. The final part focused on the exploration of Neurexin1 (NRXN1), a gene involved in synaptic functions, extensively associated with ASD. Through the use of induced pluripotent stem cells (iPSCs) this study showed that NRXN1α might affect neuronal progenitor stem cells (NPCs) proliferation, fate determination and neuronal maturation during cortical development. Our studies suggest that there is a delay in neuronal development in the systems studied. To conclude, although there are no pharmacological treatments for the cure of ASD, the early intervention, mainly during the first semester of fetal development, might help to prevent or reduce the risk for ASD.
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