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Mol Psychiatry. 2017 Aug;22(8):1140-1148. doi: 10.1038/mp.2016.51. Epub 2016 Apr 19.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Author information

1
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
2
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Department of Neuroscience and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Pediatric Neurology, Center for Neuroscience, University of Alberta, Edmonton, AB, Canada.
5
Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA, USA.
6
Departments of Psychiatry and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other 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 showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also 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 IS is required at different time points to rescue circadian behavior and 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.

PMID:
27090306
PMCID:
PMC5071102
DOI:
10.1038/mp.2016.51
[Indexed for MEDLINE]
Free PMC Article

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