The co-occurrence of Autism Spectrum Disorders (ASD) and Tuberous Sclerosis Complex (TSC) has been recognized for many years. Features of ASD are present in 25-50% of individuals with TSC, a neurodevelopmental disorder caused by mutations in tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin respectively. Tuberin and hamartin function together to inhibit mTOR signaling, which regulates protein synthesis and cell growth. In addition to being a critical regulator of cell growth, mTOR signaling plays an essential role in neural plasticity and synapse function by modulating local protein synthesis in neurons. Dr. Ramesh has identified another protein, Pam (Protein Associated with Myc), that interacts with the TSC2 protein tuberin and modulates mTOR as well. The central hypothesis of this proposal is that Pam functions as an E3 ubiquitin ligase and controls the balance of synaptic proteins. The synapse, a basic unit of function in the nervous system is the primary site of communication between neurons. Aberrant expression of Pam could perturb this balance resulting in excess or reduced neuronal connectivity. Mutations in another E3 ligase have been reported in autism associated with Angelman's syndrome. These observations, as well as the link between TSC and autism, strongly support the hypothesis that Pam could be a potential player in ASD. What this means to people with autism: This project is devoted to understanding the role of Pam in mammalian synapses as well as generating an animal model to serve as a valuable model for understanding how synaptic activity may be regulated in ASD.