Problem to Be Addressed: There has been a documented increase in the number of individuals born with autism spectrum disorder (ASD). The rise in incidence is not merely a consequence of better ascertainment of neuropsychiatric disorders. Because of this increase and because of data suggesting that ASD begins in utero, we have asked whether the maternal immune system might contribute to ASD. In particular, we have questioned whether maternal brain-reactive antibodies passing through the placenta might potentially perturb fetal brain development. We have generated monoclonal brain-reactive antibodies from blood cells of women with a child with ASD. We now propose to determine if these alter brain development in fetal mice and if we can demonstrate particular ASD characteristics associated with each antibody. Innovation: Most studies of the cause of ASD have focused on genetics. Our approach posits that some women possess brain-reactive antibodies that can perturb normal fetal brain development. While the brain is normally not exposed to circulating antibodies because of the presence of a barrier between the blood and the brain that does not allow antibodies access to the brain, the developing fetal brain does not yet have such a competent barrier. The novelty of our approach is not only to look at maternal antibody, but to isolate and clone those antibodies that can be studied individually to see which alter brain development. We now have a large panel of these antibodies, which represents a unique resource. Impact: These studies are designed to help identify pregnancies with an increased risk for an ASD child and to learn how pathogenic anti-brain antibodies alter fetal brain development. The studies address two areas of interest in the autism Research Program. They will contribute to "understanding factors underlying the heterogeneity of clinical expression" of ASD, since particular maternal brain-reactive antibodies may contribute to specific phenotypic manifestations in the offspring. These studies will also contribute to the "validation of new or existing therapeutic targets" since the data we obtain may also provide clues to the pathways that can be targeted not only by antibody, but also by genetics or by toxins or other brain insults to give rise to a child with ASD. Because they will identify pathways of neuronal development that are impaired by antibody, they may suggest therapeutic as well as prevention strategies, based on neutralizing antibody during pregnancy or elimination pathogenic.