There is no cure and limited treatment available for autism and a related disorder Angelman syndrome (AS). Both of these neurodevelopmental diseases share a common genetic link involving changes in the protein called Ube3a. When Ube3a protein is lost in nerve cells, it causes AS mental retardation. In some forms of autism, the amount of Ube3a protein is increased. Therefore, we will focus on finding a new therapy for AS and autism by discovering drugs that can control the Ube3a gene and the amount of Ube3a protein nerve cells make from this gene. We have developed a new technology that enables us to monitor the amount of Ube3a protein that is present in nerve cells. Using this technology, we will test approximately 2200 drugs, most of them already approved medications, to find candidate drugs that control the amounts of Ube3a protein in cells. Drugs that can increase or decrease Ube3a protein will be identified. In a second series of experiments, these candidate drugs will be administered to mice to determine if they can control the amount of Ube3a protein present in the brain. The two most promising candidate drugs will then be tested in mice to determine if they can improve impairments that are associated with autism and AS. This research will identify new drugs, possibly already approved by the Food and Drug Administration, that control the amount of Ube3a, a protein genetically linked to both autism and AS. These candidate drugs are anticipated to provide a new treatment therapy for autism and AS.