Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections may lead to many neurodevelopmental disorders, including autism. Although there is clearly a strong genetic component to autism, its incidence also appears to be influenced by a wide range of environmental factors. Many of these factors have in common the ability to alter immune function. Since MHCI molecules are proteins that mediate the immune response and that are also present on neurons, it is possible that changes in expression of MHCI in the developing brain lead to the cellular changes that contribute to autism. Recently, Dr. McAllister's lab has discovered that MHCI molecules negatively regulate the initial formation of connections in the developing brain. This result is particularly exciting because it implies that environmental factors that initiate an immune response could dramatically affect connectivity in the developing brain and thereby alter cognition. Since cytokines potently regulate MHCI expression in the immune system and several cytokines have been found to be upregulated in the brains of autistic children, it is possible that these cytokines alter synaptic connectivity in the developing brain by altering MHCI levels. This project will test this hypothesis. What this means for people with autism: Results from these experiments will identify whether alterations in MHCI levels could be involved in the pathogenesis of autism. Elucidating the mechanisms by which MHCI molecules act could reveal possible therapeutic targets for preventing and/or treating autism.