Project 461835

Autism Spectrum of Disorders (ASD) affect young children and last a lifetime. Mutations in >100 genes cause ASD, and this has made finding therapies a challenge. Many people with ASD respond poorly to insulin (called insulin resistance) suggesting that ASD mutations affect insulin signaling and that agents that improve insulin signaling might benefit these people. Indeed, several ASD-risk genes affect insulin signaling. Intriguingly, many ASD mutations cause proteins to misfold during their synthesis causing cellular stress. This stress activates an enzyme called PTP1B that blocks insulin signaling and many vital neuronal functions. We hypothesize that targeting PTP1B may reduce cellular stress, improve insulin signaling and ameliorate neurological deficits in many forms of ASD. In support of this hypothesis, we demonstrate that selective activation of PTP1B in PV neurons produces ASD-like behaviors (reduced social interaction and increased repetitive stereotyped behaviors) in mice. Conversely, deletion of PTP1B ameliorates ASD-like deficits. Further, we successfully used a natural compound called Trodusquemine that is a PTP1B-selective inhibitor to treat mice carrying a deletion of a rare ASD-risk gene. Here, we will test whether blocking PTP1B (either by deletion or by a drug) can improve two additional ASD mouse models. Significance: In Canada, > 1 in 68 children are diagnosed with ASD. If blocking PTP1B can improve ASD in several preclinical mouse models, this would support clinical trials of Trodusquemine to treat ASD. Trodusquemine improves insulin sensitivity and has already been used in clinical trials for obesity.