title: Elevated activation of CaMKIIα in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation.
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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Huang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Chao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Tsai
authors.affiliation: Interdisciplinary Program of Life Sciences, National Tsing Hua University Hsinchu, Taiwan.
authors.forename: Ming-Hung
authors.initials: MH
authors.lastname: Chung
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.
authors.forename: Yi-Shuian
authors.initials: YS
authors.lastname: Huang
keywords: CPEB; CaMKII; NMDAR; depotentiation; synaptic depression