Identification And Rescue Of Misregulated Insulin Signaling In A Drosophila Model Of Fragile X Syndrome

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low IQ and a range of symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we show that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain is sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated insulin signaling in the dfmr1 mutant brain. Consistent with a causal role for elevated insulin signaling in dfmr1 mutant phenotypes, expression of dfmr1 specifically in the IPCs reduced insulin signaling, and genetic reduction of the insulin pathway led to amelioration of circadian and memory defects. Furthermore we showed that treatment with the FDA approved drug metformin also rescued memory. Finally, we showed that reduction of insulin signaling is required during the pupal period to improve circadian rhythmicity, but is not required until adulthood to rescue memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.