A Cerebellar Mutant for Investigating Mechanisms of Autism in Tuberous Sclerosis
Boston Children's Hospital
Basic & Clinical
Currently there are no approved drugs that treat the core symptoms of autism, creating a huge unmet need for the millions of individuals around the world affected with this condition. One approach for identifying drugs for the core features of autism is to use validated animal models that mimic these features in behavioral paradigms. Such models can be essential tools for testing hypotheses and developing novel treatments. A genetic disease associated with a high risk of developing autism spectrum disorders is tuberous sclerosis complex (TSC). This disease occurs due to mutations in the TSC1 or TSC2 genes, which are evolutionarily well conserved. In mice these genes are called Tsc1 and Tsc2, respectively. These two genes normally put a brake on protein synthesis in cells and prevent overgrowth. When they are mutated, they result in the presence of enlarged cells and exuberant neuronal connections. Aberrant protein synthesis appears to be a mechanism involved in not only TSC, but also a number of other genetic autism syndromes. The investigators have generated a new mouse model by deleting the Tsc1 gene only in a subset of cells in the cerebellum. The cerebellum is a part of the brain that has been implicated in autism based on human studies, but mouse models that rigorously demonstrate a role for the cerebellar dysfunction leading to core features of autism are lacking. Their Tsc1 cerebellar knockout mice avoid social interactions with other animals and new social situations, similar to people with autism including difficulty in a "reversal learning" task, suggesting their restrictive/repetitive interests. Importantly, treating these mice with a small molecule (rapamycin) in early life prevents the development of these symptoms. The overall goal of this study is to understand how loss of Tsc1 function in the cerebellum leads to autism-like traits in mice. First, the study examines how the brain is wired in these mice. This will provide important insights about the brain circuits that contribute to autistic symptoms. Since these symptoms are preventable by rapamycin treatment, this mouse model provides an unprecedented opportunity to ask whether critical periods exist for development and treatment of autism-like traits in mice. Given that aberrant protein synthesis may be a common mechanism shared by several genetic causes of autism, findings from this mouse model may have important implications for other types of autism as well.