Systems Biology of Autism: The Case for the Cerebellum

One of the most important unanswered questions in autism research today is the identity of the neural circuit(s) responsible for autistic behavior. Accumulating evidence suggests that cerebellar structural and functional abnormalities may play an ongoing role in, or even act as a developmental cause of the deficits experienced by autistic persons. However, directly proving such roles for the cerebellum requires an animal model, where perturbations can be done in a controlled manner. This project involved a collaborative, multi-dimensional approach by three investigators to interrogate the role of cerebellum in autism using a mouse model. The Sahin laboratory has recreated common autism-like traits in mice by mutating a single gene (Tsc1) in a specific cell type of the cerebellum – Purkinje cells (PCs), the cerebellum’s output neuron. Importantly, treatment of these mice with an mTOR inhibitor prevents the development of autistic-like behaviors. Together with the Regehr and Wang laboratories, the overall goal of this project was to determine why mice with Tsc1 selectively eliminated from cerebellar PCs exhibit behaviors consistent with ASDs. Bringing together three investigators with complementary expertise, the experiments in this project presented an unprecedented opportunity to understand the neural circuitry of autism.