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Interactions of environment and molecular pathways on brain overgrowth in autism: Maternal inflammation and the PI3/AKT pathway

Los Angeles
State/Province Full: 
United States

It has been recently reported that some individuals with autism show premature brain overgrowth early in development. This may be the result of more brain cells, improved cell survival, or larger cell size in the developing brain. It may also be the result of specific genetic mutations such as PTEN or the Tuberous Sclerosis genes. 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. Here, we seek to understand mechanisms of MIR-induced macrocephaly in ASD. One mechanism by which genes and environment might interact in maternal inflammatory response is through the production of reactive oxygen species (ROS). While it is well known that high levels of ROS are toxic to cells, the effects of low levels of ROS are unknown. Maternal and embryonic ROS levels can be influenced by many environmental factors including viral infection and allergic/immune disorders which have also been positively associated with macrocephaly. This lab has previously shown that low levels of ROS produced by NOX enhance neural stem cell self-renewal, at least in part due to disruption of PTEN function. Here, they will determine whether there is a pathogenic link between NOX generated ROS and brain size in a rodent model. What this means for people with autism: If environmental factors result in a maternal immune response by inducing NOX and producing levels of ROS that reversibly inactivate PTEN, this inactivation of PTEN could be responsible for a widespread prevalence of brain overgrowth in autism. This can lead to potential therapeutic responses that reduce reactive oxygen species generation and possibly prevent brain overgrowth and affect PTEN signaling, perhaps partially preventing autism symptoms in some individuals at risk for autism.