Neurobiology of Lipid Signalling in the Developing Brain: Link to Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are neurodevelopmental conditions diagnosed by atypical behaviours in social interaction and communication, along with stereotyped, restricted and repetitive behaviours. The exact cause of ASDs is unclear but is likely from a combination of genetic and environmental influences. Various clinical studies have identified an association between irregular lipid signalling and ASDs.

Lipids are major components of brain cells and serve as a supply for signalling molecules such as prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is the key enzyme responsible for PGE2 production in the brain. The COX-2/PGE2 signalling pathway is essential for development and maintenance of healthy neural functions. Genetic defects or exposure to various environmental agentssuch as infections or drugscan disrupt the levels of PGE2.

However, investigation into the molecular mechanisms by which disrupted COX-2/PGE2 signalling or irregular PGE2 levels might affect the development of the nervous system and contribute to the pathogenesis of ASDs is sparse. Addressing this gap in knowledge was the main purpose of this dissertation. We found that PGE2 interacts with the key developmental Wnt signalling pathway in vitro by affecting neuroectodermal stem cell motility and proliferation (Study 1) and by promoting their differentiation into neurons (Study 2). In addition, prenatal PGE2 exposure disrupted cell density and increased migration in ASD-implicated areas of the mouse brain (Study 3). Decreased PGE2 (via COX-2-deficiency) or increased PGE2 in mice also led to abnormal microglial density and morphology (Study 4). Lastly, behavioural outcomes related to ASDs were quantified in COX-2-deficient and PGE2-exposed mice (Study 5 and 6).

Our findings support epidemiological and clinical reports implicating the COX-2/PGE2 pathway in ASDs. We provide novel evidence that disturbances in the COX-2/PGE2 pathway results in aberrant neurodevelopment, including molecular, cellular, and behavioural differences analogous to those described in ASDs. Importantly, this array of research studies is one of the first to investigate mechanisms related to ASDs in both males and females and at various developmental stages, which is greatly underrepresented in the current literature. Altogether, this dissertation exposes the COX-2/PGE2 pathway as an autism candidate pathway and offers important insight into the complex, unknown etiology of ASDs.