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Metformin ameliorates core deficits in a mouse model of fragile X syndrome

Nature Medicine volume 23, pages 674–677 (2017)Cite this article

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Abstract

Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1−/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.

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Figure 1: Chronic metformin treatment corrects the social deficit, repetitive behavior, aberrant dendritic spine morphology and exaggerated LTD in Fmr1−/y mice.
Figure 2: Chronic metformin treatment corrects macroorchidism, decreases translation and reduces the phosphorylation of upstream eIF4E effectors.

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Acknowledgements

This work is supported by the FRAXA Research Foundation, Brain Canada/FNC, a CIHR foundation grant (FDN-148423) and Brain & Behavior Research Foundation grants (24365) to N.S.; a Wellcome Trust/Royal Society Sir Henry Dale grant (107687/Z/15/Z) to C.G.G.; the Canada Research Chair Program (950-231066) to J.-C.L.; and a Brain Canada/NeuroDevNet Postdoctoral Training Award to J.P.

Author information

Author notes

  1. Ilse Gantois, Arkady Khoutorsky and Jelena Popic: These authors contributed equally to this work.

  2. Jean-Claude Lacaille, Christos G Gkogkas and Nahum Sonenberg: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montréal, Québec, Canada

    Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Ruifeng Cao, Vijendra Sharma, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Seyed Mehdi Jafarnejad, Clément Chapat & Nahum Sonenberg

  2. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada

    Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Ruifeng Cao, Vijendra Sharma, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Seyed Mehdi Jafarnejad, Clément Chapat & Nahum Sonenberg

  3. Department of Anesthesia, McGill University, Montréal, Québec, Canada

    Arkady Khoutorsky

  4. Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec, Canada

    Arkady Khoutorsky

  5. Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada

    Argel Aguilar-Valles, Erika Freemantle & Jean-Claude Lacaille

  6. Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada

    Argel Aguilar-Valles, Erika Freemantle & Jean-Claude Lacaille

  7. Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, Minnesota, USA

    Ruifeng Cao

  8. Patrick Wild Centre, University of Edinburgh, Edinburgh, UK

    Tine Pooters, Isabelle A Groves & Christos G Gkogkas

  9. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK

    Tine Pooters, Isabelle A Groves & Christos G Gkogkas

  10. Department of Physiology and Biophysics, School of Medicine, University of Colorado, Aurora, Colorado, USA

    Elizabeth A McCullagh

  11. Department of Psychology, McGill University, Montréal, Québec, Canada

    Karine Gamache & Karim Nader

Authors
  1. Ilse Gantois
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  2. Arkady Khoutorsky
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  19. Jean-Claude Lacaille
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  20. Christos G Gkogkas
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  21. Nahum Sonenberg
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Contributions

I.G., A.K. and J.P. designed the experiments, performed data analysis and wrote the manuscript. I.G., A.K., J.P., A.A.-V., E.F., R.C., V.S., T.P., A.N., S.W., S.M.J., C.C., E.A.M. and C.G.G. designed and carried out experiments. A.S., V.T.T., I.A.G. and K.G. assisted with experiments. K.N. supervised the project. J.-C.L., C.G.G. and N.S. supervised the project, designed experiments and edited the manuscript. All authors revised the manuscript.

Corresponding author

Correspondence to Nahum Sonenberg.

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The authors declare no competing financial interests.

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Supplementary Figures 1–17 and Supplementary Tables 1 and 2. (PDF 5149 kb)

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Gantois, I., Khoutorsky, A., Popic, J. et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med 23, 674–677 (2017). https://doi.org/10.1038/nm.4335

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