Autism is among the most devastating childhood disorders in terms of prevalence, morbidity, outcome, impact on the family and cost to society. Autism comprises of several different disorders commonly defined by deficits in social behaviors and interactions. These deficits prevent the development of normal interpersonal relationships of affected patients with their parents, siblings and other children. Autism is now recognized as a disorder of prenatal and postnatal brain development. Although autism is primarily a genetic disorder involving multiple genes, insights into underlying mechanisms will require a multidisciplinary approach. Recent findings in collaboration with Eric Courchesne revealed abnormal organization within normal appearing frontal cortex, a region highly implicated in this disorder. In addition, genetic analysis identified significant disturbances to genes that are consistent with the disorganization observed in autistic patients. These findings will serve as the basis for this study of the molecular mechanisms responsible for the novel pathological phenotype in autism frontal cortex. The study aims to: 1) determine whether the disorganization found in frontal cortex of autism patients is also present in other cortical brain regions, using additional postmortem brain tissue. This aim will help develop my developmental neuroanatomical knowledge and expertise; 2) perform genetic analyses to compare within the regions of disorganized and normal appearing cortex of young autistic cases. This will yield knowledge and expertise to study complex genetic disorders, such as autism; and 3) identify genetic abnormalities specifically in the disorganized cortex in the previous aims will be manipulated in cells in culture to determine their role in the proliferation of these cells and their transition into neurons. This aim may help bridge the postmortem tissue findings and the creation of a cell based model for autism. In addition, it may lead to the identification of causative factors in the molecular pathophysiology of autism that can inform translational research for drug discovery or development of methods for early diagnosis. These abnormal cortical patches are undeniably of very early developmental origin, and could be the neural defects that cause autism. Understanding the prenatal etiology and genetic and molecular mechanisms that generate pathological patches should lead to new methods for detection of early risk and prognosis, and may facilitate the development of novel therapeutics.