The majority of autistic individuals suffer from mental retardation, suggesting that cognitive impairment is a central problem in autism (Fombonne, 1999). The mechanistic basis for cognitive impairment, however, remains unclear, and currently there is no known cure. Hope for a treatment is plausible though, since patient neurons do not appear damaged or destroyed. In fact, the neuronal circuitry that is largely formed before birth is grossly normal in autistic patients. That is, the large nerve fibers appear to be in the right place. Instead, it is the fine synaptic connections on those fibers, the structural sites for neurotransmission between neurons, formed after birth, that appear disrupted in autism. These synaptic connections, and their modification by experience, are thought to underlie the fundamental mechanisms of cognitive functioning. Since these synaptic connections are highly flexible after birth and remain so in children and adults with autism spectrum disorders (ASD), we believe that drugs should be able to correct the cognitive impairments of autism and that these drugs will work by influencing the synaptic connections. In this research project, we will begin to test this belief by developing a new technology that can identify and visualize defects in synaptic connectivity at the cellular level, and then can be used for rapidly testing improvements to those defects by a high volume of possible drugs. Once we establish this technology, we will test whether any compounds from a collection of approximately 1,000 commercially approved and natural products can restore these synaptic defects to normal. Results from this study will provide: (a) direct insight on the basic cell features of autistic mental disability, (b) a biological tool that can be used for diagnosis and further drug testing, and (c) potential treatments ready for immediate therapeutic use in autism and possibly even mental retardation arising from other disorders.