Genetic and Pharmacological Modifications of Autistic-Like Behaviors in Fmr1 KO and Other Mouse Models of ASD

Fragile X syndrome (FXS) results from the loss of expression of the Fragile X mental retardation (FMR1) gene. Individuals affected by FXS experience many behavioral problems, including cognitive impairment, hyperactivity, and social anxiety. In addition from 15-25% of individuals with FXS meet the full criterion for autism spectrum disorder (ASD). A mouse model of Fmr1 deficiency (Fmr1KO) exhibits several similar behavioral phenotypes, including alterations in autistic-like behaviors such as social interactions. Identifying and evaluating targets that modify behavioral responses in the Fmr1 KO mouse therefore should help with the initial development and evaluation of therapies for FXS and ASD. Our lab has used both genetic and pharmacological tools to modify the behavior of Fmr1 KO mice. One strategy we have employed is to over-express human FMRP and determine if we rescue abnormal responses in Fmr1 KO mice. Recently we found that both social behaviors and sensorimotor gating are rescued in Fmr1 KO mice that carry the human FMR1 gene. Recent findings suggest that group 1 mGluR5 receptor function may be overactive in Fmr1 KO mice. We have explored the possibility of reducing mGluR5 signaling using pharmacological treatments and gene knockout mice can alter responses in Fmr1 KO mice. Our findings suggest that modifying mGluR 1/5 receptors can alter the behavior of Fmr1 KO mice suggesting that drugs targeting this receptor system may be useful treatments for FXS and ASD.