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.
Bibliographical noteFunding Information:
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.
- FRAGILE X syndrome
- PATHOLOGICAL physiology
- MENTAL disabilities
- ADENYLATION (Biochemistry)
- CARRIER proteins
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)