Autism Spectrum Disorders

Autism is a complex disorder of the brain that lasts throughout a person’s life and affects the ability to communicate, form relationships with others, and respond appropriately to the environment typically by 3 years of age. In the past two decades autism became a primarily disorder of brain development. The incidence of Autism Spectrum Disorders is currently 1 in 68 and it affects boys four times more often than girls. As many as 20 or more genes on different chromosomes may be involved in the disorder to various degrees and determine the severity of symptoms. Interactions between those genes in addition to environmental factors likely contribute to variable expression of autism-related traits. The multidisciplinary research program in my laboratory integrates genetics, molecular and cellular neurobiology approaches to study the link between the causative biological factors and behaviour.

Neurobiology of Lipid Signaling in Autism Spectrum Disorders

Lipids play pivotal role in the development and function of the human brain. The brain has the highest percentage of lipids in the body. Proper brain function relies on the balance between the supply of dietary lipids also known as polyunsaturated fatty acids (PUFAs) and the release of their bioactive metabolites from membrane phospholipids. While PUFAs are crucial for membrane structure and function, their metabolites, such as bioactive prostaglandin E2, are very important for the normal functioning of the brain. Growing evidence shows that altered lipid metabolic pathways during early development may be involved in the pathogenesis of autism and contribute to the variable expression of autism-related traits. The lipid signalling pathway can become defective due to genetic causes or environmental agents, such infections, air pollutants, heavy metals, pesticides, endocrine disrupting chemicals, products containing lipid analogues, and non-steroidal anti-inflammatory (NSAID) drugs. Our lab investigates the effect of abnormal lipid signaling during the critical embryonic period on proliferation, migration, aggregation, differentiation or synaptogenesis of brain cells and expression of early developmental genes.

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Lipid Components of Cell Membrane Associated with ASD

The plasma membrane phospholipids play an important role in the nervous system and serve as a supply of signaling molecules important for normal functioning and development of the brain. Research shows that abnormal lipid metabolism may play a contributing role in the pathology of autism disorders. Lipid homeostasis can be altered in autism as a result of insufficient dietary supplementation of omega-6 and omega-3 fatty acids, genetic defects, function of enzymes involved in their metabolism, or influence of various environmental agents such as drugs (misoprostol or NSAID), infections or inflammation. (Dashed arrows indicate an increase or decrease level; asterisks indicate a link to ASD). (Tamiji and Crawford 2010a, Wong et. al. 2013).
Defects in Lipid Mediators Associated with ASD

Various bioactive lipid molecules such as arachidonic acid (AA) can be normally released from membrane phospholipids by the action of phospholipase A2 (PLA2) and subsequently metabolized into various types of bioactive prostanoids. Cyclooxygenase-1 enzyme (COX-1), constitutive form, or cyclooxygenase-2 (COX-2), inducible form, converts AA to the unstable PGG2 intermediate and then to the prostanoid precursor PGH2, which is further metabolized by the prostaglandin (PG) synthase into the major lipid signaling messengers such as prostaglandins (PGE2) and other bioactive lipid metabolites such as prostanoids (PGE2, PGF2α, PGD2, PGI2) and thromboxane A2 (TXA2). (Dashed arrows indicate an increase or decrease level; asterisks indicate a link to ASD). (Tamiji and Crawford 2010a, Wong et. al. 2013).
The PGE2 Signalling Pathway

PGE2 diffuses rapidly through membranes, exerting its signalling effects by binding to E-prostanoid receptors (EP1-4). Evidence shows that it is involved in early prenatal brain development such as dendritic spine formation, synaptic plasticity or pain transmission. Clinical studies have revealed a connection between misuse of the drug misoprostol (an analogue of prostaglandin type E) during the first trimester of pregnancy and neurodevelopmental aberrations, including Mobius sequence and ASDs. Misoprostol has been proven to bind and activate EP receptors activating the PGE2 pathway. During the early stages of pregnancy (5 to 6 weeks after fertilization), the embryo is the most vulnerable to misoprostol exposure. We have previously shown that misoprostol and PGE2 can increase the intracellular level and fluctuation amplitude of calcium in neuronal growth cones, as well as reduce the number and length of neurite extensions through the activation of EP receptors. (Tamiji and Crawford 2010b, Tamiji and Crawford 2010c).

Cross-talk between PGE2 and Wnt Signalling Pathways

There is growing evidence in non-neuronal cells supporting an interaction between the PGE2 and the Wnt (wingless) pathways. Such an interaction is of particular interest since Wnts are morphogens necessary for the formation of a healthy nervous system. Our lab investigates the interaction between these two pathways in the nervous system. We have shown that PGE2 can modulate the expression of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) and change the Wnt-dependent proliferation and migration behaviour of neuroectodermal (NE-4C) stem cells. We also show that PGE2 treatment leads to earlier formation of neural stem cell clusters called neurospheres during differentiation. PGE2 also changed the expression of Wnt pathway genes during cell differentiation, including Wnt2, Wnt3, Wnt8a, Tcf4, Ccnd1, Mmp2, and Mmp9. All these genes have been linked to neurodevelopmental disorders, including ASD.  (Wong et. al. 2014)

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