Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology

UMMS Affiliation

Program in Molecular Medicine; Department of Psychiatry, Brudnik Neuropsychiatric Research Institute

Publication Date


Document Type



3' Untranslated Regions; Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Humans; Male; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; RNA, Messenger; Transcription Factors; mRNA Cleavage and Polyadenylation Factors


Biochemistry | Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Molecular Genetics


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.

DOI of Published Version



Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med. 2013 Nov;19(11):1473-7. doi: 10.1038/nm.3353. Link to article on publisher's site

Journal/Book/Conference Title

Nature medicine

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