Abnormal COX2/PGE2 Signalling in the Developing Cerebellum - A Link to Autism Spectrum Disorders

Autism spectrum disorders (ASDs) include a group of neurodevelopmental conditions that are characterized by deficits in social interaction and communication, increases in repetitive/restricted often stereotyped behaviour, and increases in anxiety. The heterogeneous nature of ASDs with regards to symptoms but also genetic profiles of ASD individuals, make understanding factors contributing to the disorder complex. However, literature suggests that ASDs arise from a combination of genetic and environmental factors. Clinical studies have suggested that abnormal lipid signalling, as a result of environmental insults can contribute to the etiology of ASDs. The phospholipid membrane of cells within the can be metabolized into lipid signalling molecules, including prostaglandins. Prostaglandin E2 (PGE2) is one of the most utilized lipid signalling molecules in the brain, involved in developmental processes such as synaptogenesis, migration, and differentiation of neuronal stem cells. Abnormal levels of PGE2, as well as COX-1 and COX-2, the rate-limiting enzymes in PGE2 synthesis have been linked to ASD. Furthermore, various environmental risk factors including exposure to heavy metals, infection/inflammation in pregnancy, exposure to pesticides, fragrances, and the use of over-the-counter medications such as aspirin and acetaminophen can affect PGE2 levels and are linked to ASD.

The exact mechanisms that link abnormal COX2/PGE2 signalling to ASD are still unclear. To help address the lack of information, in this dissertation we first examine the effect of exposure to PGE2 on differentiated neuroectodermal (NE-4C) stem cells. Further, Studies have demonstrated that the cerebellum may be important in the etiology of ASDs. Interestingly there is evidence that PGE2 can affect postnatal development of the cerebellum. We examine the effect of increases (in a maternal PGE2 injection model) and decreases (in a COX-2--KI model) in PGE2 levels on prenatal neurodevelopment. We specifically examine the effects of these increases and decreases on cytoskeletal-dependent morphology through dendritic morphology within the cerebellum. Additionally, we examine the effect of prenatal PGE2-exposure on cerebellar-dependent motor function postnatally. Given the importance of sex as a factor in examining neurodevelopmental disorders such as ASD that have a large sex bias towards males, all of our in vivo studies address the modulation of the PGE2 effect by sex.

These studies demonstrate that abnormal COX2/PGE2 signalling can affect important neurodevelopmental processes in vitro and development of the cerebellum in vivo. We observed disruptions in cytoskeletal dynamics, and changes in the expression of cytoskeletal proteins corresponding to abnormal COX2/PGE2 signalling. In PGE2-exposed mice, the changes in dendritic morphology in the cerebellum, corresponded to deficits in cerebellar motor function. Further, we found that the disruption of COX2/PGE2 affected development in a sex-dependent manner. The findings strengthen the involvement of COX2/PGE2 signalling in normal development of the brain and further suggest that abnormal COX2/PGE2 signalling as a result of exposure to environmental factors can result in neuropathologies including those found in ASDs