CART Pilot Project: Genetic and Environmental Influences on Brain Overgrowth in Autism

Project summary

Autism is a spectrum of neurodevelopmental disorders that are characterized by social and communication deficits. Currently the precise causes and the degree to which genetic and environmental factors interact to produce the syndrome are unknown. Brain overgrowth is a relatively common feature in autism and can be caused by mutations in specific genes (PTEN and TSC genes) in both autistic children and in experimental animals. Therefore, we propose to study the genetic changes caused by PTEN- and TSC-deletion using whole-genome microarray analysis and we will then compare these results with human data autistic individuals with brain overgrowth collected through the Autism Speaks AGRE database. Through these studies it is hoped that we will increase our understanding of the genetic and molecular pathways that regulates brain overgrowth and that we will identify other candidate genes for study in autism. Additionally, recent studies have demonstrated that brain overgrowth can also be caused by the interaction of environmental factors such as maternal inflammatory response (MIR) with genetic susceptibility during periods of vulnerability in fetal development. Maternal inflammatory response is simply the triggering of the immune system in pregnant mothers. Immune system activation causes the production of toxic metabolites that are designed to destroy invading organisms or materials. When excessive, this response damages surrounding healthy tissues or may be detrimental to a fetus even when produced at normal levels if it occurs at a particularly vulnerable period during brain development.

One mechanism by which genes and environment might interact in maternal inflammatory response is through the regulation of the production of reactive oxygen species (ROS). While it is well known that high levels of ROS are toxic to cells, it is less known that low levels of ROS can activate cellular pathways that promote proliferation. These ROS are produced in cells, including brain cells, by the enzyme NADPH oxidase (NOX), which in turn can reversibly inactivate certain genes which are susceptible to oxidation such as PTEN. Maternal and embryonic ROS levels can be influenced by many environmental factors such as exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. These environmental factors can generate a maternal inflammatory response. Experimental studies have demonstrated that at least some causes of MIR can produce brain overgrowth in the developing fetus.

It is our theory that environmental factors resulting in a maternal inflammatory response contribute to brain overgrowth by inducing NOX and producing levels of ROS that can reversibly inactivate PTEN. We already know that deleting the PTEN gene leads to brain overgrowth in humans and mice. Therefore, the inactivation of PTEN as a result of maternal inflammatory response could be responsible for the widespread prevalence of brain overgrowth in Autism since many environmental factors exist which can cause a maternal inflammatory response and elevated ROS levels. In addition to testing if MIR can indeed contribute to brain overgrowth and social behavior deficits in mice we will also assess whether anti-oxidant treatment or signaling pathway inhibition during pregnancy can prevent the brain overgrowth and behavior deficits caused by maternal inflammatory response.