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Behavioral Evaluation of Rat Knockout Models of ASD

State/Province Full: 
United States

The advent of transgenic technologies has revolutionized behavioral science. While mouse genetic models have been invaluable for studying underlying neurobiological mechanisms, mouse behavioral analyses have often been challenging. Until very recently, the use of rats as potential genetic models for disorders of the human CNS has not been realized because of the inability to readily manipulate their genome. Scientists at SAGE Labs have now developed a strategy for creating knockout (KO) rats and under a novel partnership with Autism Speaks are generating ones with mutation in ASD susceptibility genes. Currently rat models with mutations in Fmr1, Mecp2, Neurexin 1, Neuroligin 3, and Cacna1c are being created. The project will perform a series of behavioral evaluations to characterize all five of these new rat KO lines. Each rat KO and wild type littermates will be evaluated on a test battery composed of 10 behavioral assessments directed as ASD-related phenotypes. The battery includes assessments for ultrasonic communication, repetitive/preservative responding in marble bury and grooming assays, and social interactions in a direct interaction test and three-chamber arena. In addition, assays for anxiety-like responses and cognition, as well as a number of important control assays for activity and olfactory function are employed. The research team expects to observe a number of ASD-related phenotypes similar to what is observed in KO mice with mutations in the same genes; however, they also expect to observe unique abnormalities because the behavioral responses of rats are more robust and complex for a number of these traits. The findings from this study will be a critical first step to establishing the utility of these KO rat lines for future use in translational projects directed toward evaluating potential new treatments for ASD.