Although what causes autism spectrum disorders is still unclear, imaging studies have demonstrated that certain brain areas are enlarged while others are reduced. This suggests that abnormalities in the control of size and shape of brain cells and the extent of their contacts – called pruning- with other brain cells play an important role in this effect. The main goal of this application is to investigate the link between molecules that are implicated in regulating developmental axon pruning and the gene that causes fragile X syndrome, a common form of inherited autism-related disorders. Dr. Cheng and colleagues have recently identified two molecules: Sema3F and its receptor, Plexin-A3, as key regulators for stereotyped axon pruning of hippocampal mossy fibers in the fragile X knockout mouse. By using the most advanced technologies, the investigators plan to determine whether the neuropathological deficit in the fragile X knockout mouse is caused by changes in expression of Sema3F and Plexin-A3. Significance: The ultimate goal of these studies is to understand the molecular and cellular mechanisms of developmental axon pruning and provide a therapeutic basis for treating human neurodevelopmental disorders including autism spectrum disorders.