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

• Published in: Frontiers in cellular neuroscience 2014-11, Vol.8, p.367-367
• Main Authors: Huang, Wen-Hsuan, Chao, Hsu-Wen, Tsai, Li-Yun, Chung, Ming-Hung, Huang, Yi-Shuian
• Format: Article
• Language: English
• Subjects: Neuroscience
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2014.00367

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.