About this item:

307 Views | 174 Downloads

Author Notes:

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 Fig. 4a–b. J.M.A. performed the electrophysiology experiments in Supplementary Fig. 4c–e. S. Anilkumar and S.C. performed spine density analysis in Fig. 1e,f and Supplementary Fig. 5a–b.

M.I. created and tested the CPEB antibody used in Supplementary Fig 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 Fig. 2a–b. 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.

The authors declare no competing financial interests.

We thank N. Dawra for technical assistance, P. Lombroso and C. Proud for kind gifts of antibodies, J. Pelletier for the kind gift of hippuristanol, and members of the Richter lab for helpful discussions.

Subjects:

Research Funding:

T.U. and N.G.F. gratefully acknowledge fellowships from the FRAXA Research Foundation.

J.A.H. was supported by NIH-NRSA Postdoctoral Fellowship F32GM095060.

This work was supported by NIH grants GM46779 and NS079415 to J.D.R. and MH086509 to S. Akbarian.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • BIOCHEMISTRY & MOLECULAR BIOLOGY
  • CELL BIOLOGY
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • MENTAL-RETARDATION PROTEIN
  • XENOPUS OOCYTE MATURATION
  • LONG-TERM POTENTIATION
  • CAMKII MESSENGER-RNA
  • T-MAZE ALTERNATION
  • CYTOPLASMIC POLYADENYLATION
  • SYNAPTIC PLASTICITY
  • TRANSLATIONAL CONTROL
  • WORKING-MEMORY
  • MOUSE MODEL

Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology

Show all authors Show less authors

Journal Title:

Nature Medicine

Volume:

Volume 19, Number 11

Publisher:

, Pages 1473-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2013 Nature America, Inc.

Export to EndNote