Environmental and genetic risk factors in Autism Spectrum Disorder: a stereological study
Date
2020-07-15Author
Rosati, Silvia
Metadata
Show full item recordUsage
This item's downloads: 170 (view details)
Abstract
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.