It is becoming increasingly clear to researchers and clinicians that the neurotransmitter serotonin plays an important role in autism. Clinically, drugs that increase serotonin levels in autistic patients help to alleviate some symptoms of the disorder. Molecular, genetic and clinical research demonstrates that variation in the serotonin transporter (SERT) are related to an increased risk of autism. However, the mechanism by which SERT activity is regulated is not well characterized. Studies by Dr. Sutcliffe and others have begun to identify several mechanisms as well as possible genes that might lead to an increase in serotonin transporter activity. This study will build on NIH funded research that examines the role of SERT activity and autism spectrum disorders. Specifically, Dr. Sutcliffe and his colleagues have found that a particular form of a protein named integrin beta3 is associated both with autism and with elevated SERT activity. The gene Leu33Pro (Pro 33) codes for this form of integrin beta3. This grant will allow Dr. Sutcliffe's team to build on their work by funding a program to create a gene “knock-in” mouse model, creating mice that carry the Pro33 variant of the integrin beta3 gene. The researchers will use this mouse model to study how the Pro33 variant of integrin beta3 affects SERT activity and serotonin levels in mice carrying this genetic mutation. What this means for people with autism: Compounds which target the SERT receptor are currently used to treat autism; however, the mechanism by which serotonin activity is regulated through this receptor is not well described. This study will allow researchers to better understand the mechanisms linking serotonin, the SERT receptor and autism. In particular, it will create a mouse model to tease apart how a variant of a gene for the protein integrin beta3 affects serotonin transporter activity. Having such a model will allow the researchers to study the influence this gene has in development and, potentially, on pharmacological therapies.