Abnormal Lipid Signalling in the Developing Mouse Brain: Implications in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, currently characterized by difficulties in social communication, delayed speech and language, and appearance of restricted and repetitive sensory-motor behaviours. Currently, there are many etiological factors, both genetic and environmental, that have been involved in its manifestation, including the lipid signaling pathway. The brain is rich in lipids, and the plasma membrane acts as a reservoir of bioactive molecules such as Prostaglandin E2 (PGE2), a lipid signaling molecule important for normal brain development and function. PGE2 is converted by cyclooxygenase-1 and -2 (COX-1 and -2) enzymes, a downstream action following release of arachidonic acid from the plasma membrane. Various genetic and environmental factors can influence the level of PGE2 and have been identified for their involvement in increased ASD-risk. However, the exact mechanisms behind this relationship are not well known, and thus the current dissertation aims to contribute to this gap in knowledge with four studies in vivo in the mouse brain. Using mouse models, we investigated the effects of maternal PGE2 administration (PGE2-injected) and gene knockdown of COX-1 and COX-2 enzymes (COX-1-/- and COX-2-/-) at E16 and E19, on sex- and age-dependent expression of developmental genes and proteins, global analyses of biological pathways, and characterization and analysis of dendritic spines morphology at P25. These studies established that aberrations in the COX/PGE2 signalling pathway result in differential expression of many genes and pathways involved in neurodevelopment and ASD etiology. We found abnormal age- (i.e. Mmp7 and Wnt2, Spn, Actb) and sex-dependent (i.e. Spn, Actb) gene and protein expression of developmental and synaptic functions, sex-specific enlargement of mushroom spines in cerebellar neurons, and ASD genes that are dysregulated throughout development (i.e. Glo1, Gabra2, Grm5). Interestingly, novel in vivo findings in mouse models of PGE2-administration and COX-2-/- (high and low levels) both confirmed an interaction between COX-2/PGE2 and Wnt pathway particularly at the E16 stage of development. The current findings strengthen the involvement of abnormal COX/PGE2 signalling during early brain development, and thus, many genes and environmental exposures during gestation can act on different constituents of the COX/PGE2 pathway, and result in neurological conditions such as ASD.