Genetic and environmental factors and neurodevelopmental disease

Several factors have been implicated in the etiology of neurodevelopmental disorders. The aim of this dissertation was to analyze the effects of genetic and environmental factors on neural cell development. Canavan Disease (CD) is a genetic neurodegenerative disease, caused by a deficiency in the enzyme aspartoacylase (ASPA). Since, it is still undefined how ASPA deficiency affects neural cell development. I investigated the effects of ASPA deficiency on early postnatal brain maturation in CD mice and wild-type (WT) mice. ASPA levels in WT mice displayed an expression pattern that correlates well with oligodendrocyte development, suggesting a role for ASPA in oligodendrocyte development and myelination. A sustained expression of progenitor cell markers, accompanied by decreased expression of markers for immature and mature neurons and defects in oligodendrocyte maturation and myelinogenesis was seen in CD mice brains. In parallel, a decrease in myelin proteins and an altered ultrastructure, along with astrogliosis, were also seen. Our findings suggest that, in early postnatal development, ASPA deficiency primarily affects neurons. These effects result in impaired oligodendrocyte maturation leading to dysfunctional myelination.;A maternal infection was mimicked by administering two consecutive intraperitoneal injections of lipopolysaccharide (LPS) at embryonic (E) days 15-16. The effect of a maternal exposure to LPS on neural cell development at these gestational ages was then studied in embryonic and postnatal brains. A significant increase in pro-inflammatory cytokines was observed in both maternal serum and fetal brains, following maternal injections with LPS, dramatically influencing neuronal cell migration, which may subsequently lead to improper brain development. Furthermore, a decrease in progenitor cell markers such as nestin and sox2 was observed. These findings suggest that maternal inflammation during mid/late gestation may delay neural cell development and subsequently perturbs the formation and organization of the fetal cerebral cortex.;Using these two models, either genetic or environmental, I have shown that both have detrimental consequences on specific cell populations, early in brain development leading to improper brain wiring and neurodevelopmental disorders.