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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology

Nature Medicine volume 19, pages 1473–1477 (2013)Cite this article

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Abstract

Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element–binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1−/y; Cpeb1−/− double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1−/y mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.

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Figure 1: Interplay between FMRP and CPEB1 in the brain.
Figure 2: Cpeb1 deletion ameliorates FXS-related behavioral abnormalities.

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Acknowledgements

We thank N. Dawra for technical assistance, P. Lombroso (Yale University) and C. Proud (University of Southampton) for kind gifts of antibodies (STEP and eEF2, respectively), J. Pelletier (McGill University) for the kind gift of hippuristanol and members of the Richter lab for helpful discussions. T.U. and N.G.F. gratefully acknowledge fellowships from the FRAXA Research Foundation. J.A.H. was supported by US National Institutes of Health NRSA Postdoctoral Fellowship F32GM095060. This work was supported by NIH grants GM46779 and NS079415 to J.D.R. and MH086509 to S. Akbarian.

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Author notes

  1. Tsuyoshi Udagawa, Mira Jakovcevski, Hanoch Kaphzan, Kentaro Nagaoka & Schahram Akbarian

    Present address: Present addresses: Department of Neurology, Nagoya University School of Medicine, Nagoya, Japan (T.U.), Max Planck Institute of Psychiatry, Munich, Germany (M.J.), Laboratory for Neurobiology of Psychiatric Disorders, Sagol Department of Neurobiology, University of Haifa, Mount Carmel, Haifa, Israel (H.K.), Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan (K.N.), and Friedman Brain Institute, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA (S.A.).,

  2. Tsuyoshi Udagawa, Natalie G Farny and Mira Jakovcevski: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Tsuyoshi Udagawa, Natalie G Farny, Maria Ivshina, Kentaro Nagaoka, Lori J Lorenz & Joel D Richter

  2. Department of Psychiatry, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Mira Jakovcevski & Schahram Akbarian

  3. Center for Neural Science, New York University, New York, New York, USA

    Hanoch Kaphzan & Eric Klann

  4. Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA

    Juan Marcos Alarcon

  5. Center for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine and National Center for Biological Sciences, Bangalore, India

    Shobha Anilkumar & Sumantra Chattarji

  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Jessica A Hurt

  7. Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA

    Vijayalaxmi C Nalavadi & Gary J Bassell

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  1. Tsuyoshi Udagawa
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Contributions

T.U. and J.D.R. conceived of the initial project with much input from L.J.L. T.U., N.G.F. and M.J. designed and performed the majority of the experiments. H.K. and E.K. performed the electrophysiology experiments in Figure 1c,d and Supplementary Figure 4a,b. J.M.A. performed the electrophysiology experiments in Supplementary Figure 4c–e. S. Anilkumar and S.C. performed spine density analysis in Figure 1e,f and Supplementary Figure 5a,b. M.I. created and tested the CPEB antibody used in Supplementary Figure 2f. J.A.H. performed the bioinformatics analysis in Supplementary Table 1. V.C.N. and G.J.B. performed the immunocytochemistry analysis in Supplementary Figure 2a,b. T.U., N.G.F., M.J., K.N. and S. Akbarian contributed to the behavioral experiments in Figure 2. N.G.F. and J.D.R. wrote the manuscript. All authors contributed to interpretation and discussion of results and to editing of the manuscript.

Corresponding author

Correspondence to Joel D Richter.

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Udagawa, T., Farny, N., Jakovcevski, M. et al. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19, 1473–1477 (2013). https://doi.org/10.1038/nm.3353

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