Deletion of CPEB3 Enhances Hippocampus-Dependent Memory via Increasing Expressions of PSD95 and NMDA Receptors

Chao, Hsu; Tsai, Li Yun; Lu, Yi-Ling; Lin, Pei; Huang, Wen Hsuan; Chou, Hsin Jung; Lu, W. T.; Lin, Hsiu Chen; Lee, Ping Tao; Huang, Yi

doi:10.1523/jneurosci.3043-13.2013

Cited by 72 publications

(107 citation statements)

References 53 publications

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“…It is quite possible however that in addition to the AMPAR, other, as yet un-identified, targets of CPEB3 might also contribute to the impairments of the CPEB3 CKO mice. Indeed it has been recently suggested that CPEB3 also regulates the expression of post-synaptic density 95 protein (PSD95) (Chao et al, 2013), a protein that is crucial both for synaptic function and behavioral learning and memory (Skibinska et al, 2001;Muller et al, 2000). Our findings therefore indicate that a subset of newly synthesized CPEB3 targets, including GluA1 and GluA2, play a role in the remodeling process involved in the persistence of longterm memory.…”

Section: Misregulation Of Ampa Receptor Translation In Cpeb3 Cko Micementioning

confidence: 54%

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The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

Fioriti¹,

Myers²,

Huang³

et al. 2015

Neuron

176

219

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Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory.

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Section: Misregulation Of Ampa Receptor Translation In Cpeb3 Cko Micementioning

confidence: 54%

“…A recent study by Chao et al (2013) has found that CPEB3 null mice have aberrant memory consolidation. These total knockout animals have decreased locomotor activity and slightly increased anxiety compared to control animals.…”

Section: Misregulation Of Ampa Receptor Translation In Cpeb3 Cko Micementioning

confidence: 99%

The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

Fioriti¹,

Myers²,

Huang³

et al. 2015

Neuron

176

219

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“…The molecular machinery controlling local protein synthesis has been best studied in vertebrate oocyte development during which members of the cytoplasmic polyadenylation element binding (CPEB) protein family, in concert with other RNA-binding proteins, control the temporal expression of maternal RNAs (8,9). More recently, CPEB proteins also have been found to be expressed in adult nervous systems (10)(11)(12)(13) where they are thought to be involved in synaptic plasticity and LTM (12,(14)(15)(16)(17), suggesting evolutionary conservation of the mechanism of local translation across species, tissues, and developmental stages.…”

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confidence: 99%

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

Stepien

Oppitz

Gerlach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Localized protein translation is critical in many biological contexts, particularly in highly polarized cells, such as neurons, to regulate gene expression in a spatiotemporal manner. The cytoplasmic polyadenylation element-binding (CPEB) family of RNA-binding proteins has emerged as a key regulator of mRNA transport and local translation required for early embryonic development, synaptic plasticity, and long-term memory (LTM). Drosophila Orb and Orb2 are single members of the CPEB1 and CPEB2 subfamilies of the CPEB proteins, respectively. At present, the identity of the mRNA targets they regulate is not fully known, and the binding specificity of the CPEB2 subfamily is a matter of debate. Using transcriptome-wide UV cross-linking and immunoprecipitation, we define the mRNA-binding sites and targets of Drosophila CPEBs. Both Orb and Orb2 bind linear cytoplasmic polyadenylation element-like sequences in the 3′ UTRs of largely overlapping target mRNAs, with Orb2 potentially having a broader specificity. Both proteins use their RNA-recognition motifs but not the Zinc-finger region for RNA binding. A subset of Orb2 targets is translationally regulated in cultured S2 cells and fly head extracts. Moreover, pan-neuronal RNAi knockdown of these targets suggests that a number of these targets are involved in LTM. Our results provide a comprehensive list of mRNA targets of the two CPEB proteins in Drosophila, thus providing insights into local protein synthesis involved in various biological processes, including LTM.CPEB | CLIP | Orb2 | translation | long-term memory

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“…Although several forms of LTP and LTD in the adult SC-CA1 KO synapses appear normal (Chao et al, 2013), we identified a specific type of synaptic depression, 3 min of 5-Hz stimulus-evoked DPT, that is impaired without CPEB3. This defect was ameliorated by transiently inhibiting the activity of CaMKIIα.…”

Section: Discussionmentioning

confidence: 87%

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

Huang

Chao

Tsai

et al. 2014

Front. Cell. Neurosci.

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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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Deletion of CPEB3 Enhances Hippocampus-Dependent Memory via Increasing Expressions of PSD95 and NMDA Receptors

Cited by 72 publications

References 53 publications

The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

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

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