Defects of Lipid SIgnalling in Early Neuronal Development and the Implications in Autism Spectrum Disorders

Background: Autism is a neurodevelopmental disorder caused by many genes in addition to the contributing environmental factors, which together determine the broad severity of autism phenotype. Recent literature suggests that defects in lipid signalling pathways contribute to the pathology of autism spectrum disorder (ASD). The plasma membrane phospholipids serve as a supply of bioactive molecules such as prostaglandins E2 (PGE₂) important for normal function of the brain. Abnormalities in lipid metabolism due to oxidative stress, infection or inflammation, events that increase the level of PGE₂, have been linked with malformations in the nervous system resulting in ASD. Moreover, increased level of fatty acid metabolites have been reported in many cases of ASD. Interestingly, recent studies have also shown a cooperative regulation of PGE₂ signaling with the early developmental pathways such as wingless (Wnt). Taken together these studies provide strong evidence for the important role of lipids in the nervous system. Our study will further investigate the role of PGE_2­ in early neuronal development.

Objectives: We have previously shown that PGE₂ can interfere with cell function in vitro via modulation of calcium dynamics in neuronal cells. In this study we use an in vivo system to investigate (1) the molecular mechanisms associated with concentration-dependent PGE₂ signalling in the nervous system, and (2) its interaction with other pathways during early development.

Methods: We use brain tissues derived from mice deficient in COX-1^-/- and COX-2^-/- (enzymes that synthesize PGE₂) to detect gene expression using microarray technology. Wild-type mice administered with exogenous PGE₂ during a critical prenatal stage were also studied. Custom Taqman plates for real-time PCR encompassing selected PGE₂ and Wnt-target genes were used to observe differences in gene expression. Moreover, expression of affected proteins was studied using Western blot. We tested the PGE₂ effects on brains derived from the embryonic days 16.5 and 19, and postnatal day 8.

Results: We detected various differentially expressed genes found in the COX-1^-/- and COX-2^-/- mice with critical neurodevelopmental functions, such as modulators of cell migration, signaling molecules during early development, neuronal differentiation and maturation. Wild-type mice exposed to various doses of PGE­₂ also show differentially expressed genes involved in neuronal synapses, and morphology of dendritic spines.

Conclusions: In this study, we found that abnormalities in the lipid signalling pathway as a result of genetic defects (Cox-1^-/- and Cox-2^-/-) and using exogenous drugs to alter the PGE₂ signaling pathway, caused changes in expression levels of crucial neurodevelopmental genes during early stages of brain development. Dysregulation of important functioning genes may give some insight to the pathology of ASDs.