Approximately one in every hundred children in the United States is diagnosed with autism: a group of developmental conditions that cause unusual behavior. Autism has a genetic basis, however the specific causes for autism are still obscure. The ultimate goal of this project is to identify genes that lead to autism when impaired, and to develop a system to assess novel treatments for the condition.
Although autism is diagnosed in the first years of life, it is currently not known what events trigger autism symptoms and when they initiate. Addressing these questions requires invasive procedures that are of course not possible to apply to humans. Therefore, we have generated novel mouse models with a chromosomal lesion that occurs in patients with autism - deletion of a 27-gene region of chromosome 16 referred to as 16p11.2. People with this deletion show variable behavioral symptoms including autism, language delay, and motor delay. Mice with this deletion have abnormalities in several behaviors and brain structures, and therefore provide direct evidence that deletion of 16p11.2 genes causes autism-like features. Interestingly, neonatal mice have pronounced motor deficits that precede the autism-like phenotypes in the adult, meaning that autism diagnosis and treatment should start immediately after birth, much earlier than is the case currently.
In this study I will assess the development of the brain in mouse embryos with the 16p11.2 deletion and identify the initial impairments that lead to autism-like behaviors. Following this stage, I will establish a cellular assay that will allow me to rapidly test the presence of this initial impairment. To narrow down the genes that cause developmental impairments, I will use this cellular assay to test for the presence of the developmental impairment in mice with smaller deletions of the 16p11.2 region. In the next stage, I will use mice with small duplications of the region and test if, by adding just the specific genes back, I can rescue the developmental impairments of the full deletion. In the last stage, I will test if rescuing the developmental impairment also rescues the behavioral impairments.
By doing so, I will not only define the specific genes causing the autism-like behaviors, but I will also provide a proof of principle for the ability of this approach to identify novel treatments for autism. For example, I can use the same approach to rapidly screen multiple drugs, identify those that rescue the cellular phenotype of the deletion, and test if treatment with these drugs results in rescue of the behavioral impairments later on.
This project will result in novel methods for autism diagnosis, in identification of molecular mechanisms that lead to autism when impaired, and in a methodology to rapidly assess novel treatments for autism.