Abstract
Cytoplasmic polyadenylation element binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that confines the strength of glutamatergic synapses by translationally downregulating the expression of multiple plasticity-related proteins (PRPs), including the N-methyl-D-aspartate receptor (NMDAR) and the postsynaptic density protein 95 (PSD95). CPEB3 knockout (KO) mice exhibit hippocampus-dependent abnormalities related not only to long-term spatial memory but also to the short-term acquisition and extinction of contextual fear memory. In this study, we identified a specific form of NMDAR-dependent synaptic depotentiation (DPT) that is impaired in the adult CPEB3 KO hippocampus. In parallel, cultured KO neurons also exhibited delayed morphological and biochemical responses under NMDA-induced chemical long-term depression (c-LTD). The c-LTD defects in the KO neurons include elevated activation of calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα), increased Ser831 phosphorylation of GluA1 and slow degradation of PSD95 and GluA1. Because transient pharmacological suppression of CaMKIIα activity during the DPT-initiating phase successfully reversed the LTP in the KO hippocampus, DPT and c-LTD in the two different systems shared common molecular defects due to the absence of CPEB3. Together, our results suggest that CPEB3 deficiency imbalances NMDAR-activated CaMKIIα signaling, which consequently fails to depress synaptic strength under certain stimulation conditions.
Highlights
The cytoplasmic polyadenylation element binding protein (CPEB) family of RNA-binding proteins and translational regulators contains four members in vertebrates, that is, CPEB1, CPEB2, Cytoplasmic polyadenylation element binding protein 3 (CPEB3), and CPEB4, all of which are expressed in the brain (Wu et al, 1998; Theis et al, 2003; Huang et al, 2006; Chen and Huang, 2012)
CPEB3 neither interacts with the cleavage and polyadenylation specificity factor (CPSF) nor requires the AAUAAA hexanucleotide for translational activation (Huang et al, 2006; Wang and Huang, 2012), it has been reported that the monoubiquitination of CPEB3 by neuralized1 switches CPEB3 from a repressor to an activator that increases the polyadenylationinduced synthesis of the subunits of the α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors
CPEB3 KO NEURONS RESPOND MORE SLOWLY TO C-long-term depression (LTD)-INDUCED MORPHOLOGICAL AND BIOCHEMICAL CHANGES In our previous study, we identified that the dendritic spines of CPEB3 KO pyramidal neurons are slightly enlarged
Summary
The cytoplasmic polyadenylation element binding protein (CPEB) family of RNA-binding proteins and translational regulators contains four members in vertebrates, that is, CPEB1, CPEB2, CPEB3, and CPEB4, all of which are expressed in the brain (Wu et al, 1998; Theis et al, 2003; Huang et al, 2006; Chen and Huang, 2012). CPEB3 neither interacts with the cleavage and polyadenylation specificity factor (CPSF) nor requires the AAUAAA hexanucleotide for translational activation (Huang et al, 2006; Wang and Huang, 2012), it has been reported that the monoubiquitination of CPEB3 by neuralized switches CPEB3 from a repressor to an activator that increases the polyadenylationinduced synthesis of the subunits of the α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (i.e., the GluA1 and GluA2 subunits of AMPARs; Pavlopoulos et al, 2011) It is unclear whether neuronal activity regulates this modification, in which the lysine residue of CPEB3 is conjugated to ubiquitin and how the monoubiquitinated CPEB3 promotes polyadenylation. CPEB1-controlled translation plays important roles in development, the cell cycle, neuronal plasticity and cellular senesce (see Ivshina et al, 2014 for review), yet the physiological functions of CPEBs 2–4 have only just begun to emerge
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