Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology

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 protein FMRP. FMRP and 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 Cpeb−/− double knockout mice displayed significant amelioration of biochemical, morphological, electrophysiological, and behavioral phenotypes associated with FXS. Acute depletion of CPEB in the hippocampus of Fmr1 -/y mice rescued working memory deficits, demonstrating reversal of this FXS phenotype in adults. Finally, we find that FMRP and CPEB 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 CPEB is necessary for normal neurologic function.

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…In line with this observation, genetic or pharmacological reduction of central molecules involved in the regulation of general mRNA translation (mTOR [121], S6K1 [111], tuberous sclerosis 2 [160]) and molecules involved in the mRNA translation of select targets (cytoplasmic Poly(A)-binding protein [161]) have been used successfully in the mouse model to rescue many phenotypes. Future studies will have to show if general reduction of mRNA translation is a safe therapeutic strategy in humans.…”

“…Moreover, it will be important to identify more robust and reliable behavioral defects. Here, recent advances in analyzing social behavior and social interactions in FXS mice may hold some promise [119,161,212].…”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…While control mice take more time or even refuse to enter the dark compartment, because they associate it with the shock of their paws, the Fmr1 KO mice show a range of behavioral responses. It has been reported that the Fmr1 KO mice showed a deficit in associative learning Michalon et al 2012), but also normal performance (Bakker 1994;Dolen et al 2007;Veeraragavan et al 2012;Udagawa et al 2013). However, memory extinction was exaggerated in the Fmr1 KO mice (Dolen et al 2007;Michalon et al 2012), as observed by shorter latencies to enter the dark compartment.…”

A fly trap mechanism provides sequence-specific RNA recognition by CPEB proteins

“…Initially identified as maternal mRNA regulators during early embryonic development (Richter and Lasko 2011;Weill et al 2012), it is now clear that CPEBs are key mediators of cellular homeostasis in somatic tissues, regulating important biological processes such as cell proliferation, senescence, cell polarity, and synaptic plasticity. Consequently, when misregulated, they contribute to the development of a variety of pathological manifestations, such as tumor development, memory defects, and insulin resistance (Berger-Sweeney et al 2006;Alexandrov et al 2012;Ortiz-Zapater et al 2012;Weill et al 2012;Udagawa et al 2013).…”