Elevated activation of CaMKIIα in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation

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 (...

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Published inFrontiers in cellular neuroscience Vol. 8; p. 367
Main Authors Huang, Wen-Hsuan, Chao, Hsu-Wen, Tsai, Li-Yun, Chung, Ming-Hung, Huang, Yi-Shuian
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 03.11.2014
Subjects
Neuroscience
depotentiation
NMDAR
CaMKII
CPEB
synaptic depression
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Summary: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.
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This article was submitted to the journal Frontiers in Cellular Neuroscience.
Edited by: Egidio D`Angelo, University of Pavia, Italy
Reviewed by: Hermona Soreq, The Hebrew University of Jerusalem, Israel; Tansu Celikel, Radboud University Nijmegen, Netherlands
Wen-Hsuan Huang and Hsu-Wen Chao have contributed equally to this work.
ISSN:1662-5102
1662-5102
DOI:10.3389/fncel.2014.00367