Project Summary Autism Spectrum Disorders (ASDs) are characterized by a range of reported deficits and impairments. However, detailed knowledge about their underlying mechanisms and explanatory models is currently lacking. A novel concept, supported by growing evidence, is that autism may well be primarily a disorder of prediction. Impairments of structural and functional connectivity reported in children with ASD are entirely consistent with this concept. The brain processes information by constantly making predictions about future developments in the surrounding environment, based on information from previous experience. Violations of expectations are used by the brain to adjust and make future more accurate predictions as part of the learning process. Impairments in this function may be among the key underlying core deficits in ASD. Of direct relevance to this concept, we have recently discovered a new mechanism for predictive learning in the visual cortex, which acts through modulation of persistent activity (neuronal activity, which lasts beyond the time of initial sensory stimulus). Persistent activity functions to encode information about the timing of prospective salient events, and is hypothesized to be the underlying cellular basis of working memory. Since Fragile X Syndrome, like other forms of ASDs, is characterized by impairment of structural and functional circuit connectivity, there is a critical need to establish how these aberrations of circuit connectivity lead to impaired neural activity and predictive learning in ASDs. To address this need, we will first identify impaired synaptic connections within the cortical microcircuit of Fragile X mice. Second, we will test the hypothesis that predictive coding is impaired in Fragile X mice. Finally, we will establish a causal link between impaired persistent activity and aberrant visual perception and learning in Fragile X mice. The results of these studies are expected to help establish a strong evidence- based framework for systematic characterization of additional single gene mutations associated with ASD, which may ultimately lead to potential development of targeted circuit-specific therapies for successful treatment of autism.