Cell
Volume 147, Issue 6, 9 December 2011, Pages 1369-1383
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Article
Neuralized1 Activates CPEB3: A Function for Nonproteolytic Ubiquitin in Synaptic Plasticity and Memory Storage

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Summary

The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), a regulator of local protein synthesis, is the mouse homolog of ApCPEB, a functional prion protein in Aplysia. Here, we provide evidence that CPEB3 is activated by Neuralized1, an E3 ubiquitin ligase. In hippocampal cultures, CPEB3 activated by Neuralized1-mediated ubiquitination leads both to the growth of new dendritic spines and to an increase of the GluA1 and GluA2 subunits of AMPA receptors, two CPEB3 targets essential for synaptic plasticity. Conditional overexpression of Neuralized1 similarly increases GluA1 and GluA2 and the number of spines and functional synapses in the hippocampus and is reflected in enhanced hippocampal-dependent memory and synaptic plasticity. By contrast, inhibition of Neuralized1 reduces GluA1 and GluA2 levels and impairs hippocampal-dependent memory and synaptic plasticity. These results suggest a model whereby Neuralized1-dependent ubiquitination facilitates hippocampal plasticity and hippocampal-dependent memory storage by modulating the activity of CPEB3 and CPEB3-dependent protein synthesis and synapse formation.

Highlights

► Mouse E3 ubiquitin ligase Neuralized1 facilitates synaptic plasticity and memory storage ► Neurl1-mediated ubiquitination increases AMPAR synthesis and synaptic spine number ► Neurl1-mediated ubiquitination directly activates the translational regulator CPEB3 ► Ubiquitinated CPEB3 induces the production of AMPAR and dendritic spine formation

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