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Concerted Impact of Genetic Susceptibility and Maternal Autoantibodies in a Rat Model of Autism

Current literature estimates the genetic heritability of ASD to be approximately 50% and the remaining risk is thought to be due to environmental factors. The majority of this genetic risk is found in common genetic variants, not rare inherited or de novo mutations. To promote the development of safe, effective interventions and treatments to reduce symptoms of ASD, animal models that truly represent the human clinical profile are needed.  Such a model can be achieved through the incorporation of genes that are found to be associated with ASD combined with ASD-specific biologic profiles. This will aid in the development and testing of relevant therapeutic strategies in the future.

Recent advances in genetic technology have made possible the development of rats with autism-associated genes to be inserted or deleted into the rat genome. However, of the rats generated thus far, only the Met knockout rat represents a common genetic variant that is susceptible to environmental challenges; this rat has yet to be utilized for ASD research. It is therefore the goal of the investigators to develop a gene x environment ASD rat model by first validating that the heterozygous Met knockout in rats results in decreased MET receptor expression akin to the human mutation. They will then test a specific gene x environment interaction in this newly created rat model.  They have chosen the MET-heterozygous rat because MET controls how strong the immune response is after stimulation. Thus, the researchers will take advantage of their previous work that described the presence of maternal autoantibodies to proteins in the fetal brain that are highly associated with ASD, and combine this biologic condition with the reduced production of MET (which reduces immune regulation), to recreate what they have seen in the human clinical population in a subset of mothers whose children have ASD.  The investigators hypothesize that a genetic risk factor, represented by reduced MET production, when combined with an environmental challenge (immune challenge with MAR autoantigens) will result in an animal model that clinically represents MAR autism. Thus, they will measure the susceptibility to development of maternal anti-brain antibodies in the context of the Met heterozygous genotype to determine how this environmental insult affects behavior in the offspring. Lastly, they will define the consequences of Met x autoantibody interaction in the brains of the offspring. The researchers hypothesize that there will be a decrease in MET receptor expression that will in turn increase the susceptibility of the female rats for developing maternal anti-fetal brain antibodies. Furthermore, the combination of the Met mutation and maternally derived autoantibodies in the brain of offspring will result in more severe autism related behaviors and neuroanatomical differences compared to controls.