Expression of Constitutively Active CREB Protein Facilitates the Late Phase of Long-Term Potentiation by Enhancing Synaptic Capture

Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Cell (Impact Factor: 32.24). 04/2002; 108(5):689-703. DOI: 10.1016/S0092-8674(02)00657-8
Source: PubMed


Restricted and regulated expression in mice of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons lowers the threshold for eliciting a persistent late phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This L-LTP has unusual properties in that its induction is not dependent on transcription. Pharmacological and two-pathway experiments suggest a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of L-LTP by a weak stimulus. Our analysis indicates that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provides insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.

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    • "Manipulation of CREB produces severe alterations in late phase-LTP (Bourtchuladze et al., 1994; Barco et al., 2002, 2005; Alarcon et al., 2004). Sleep loss for 8 h has been found to reduce the gene expression of CREB (Guzman-Marin et al., 2006). "
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    ABSTRACT: We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treatedwith caffeine in drinking water (0.3 g/l) for four weeks before they were REMsleep-deprived for 24 h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylatedand total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation.
    Full-text · Article · Mar 2016 · Molecular and Cellular Neuroscience
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    • "Unlike early-phase LTP, late phase LTP (L-LTP) requires gene expression and protein synthesis (Frey et al., 1993; Sweatt, 1999). The expression of L-LTP requires the participation of signalling molecules, including calcium/calmodulin kinase IV (CaMKIV) and mitogen-activated protein kinase/extracellular signal-related kinase, which phosphorylate cAMP response elementbinding protein (CREB) (Barco et al., 2002; Bramham & Messaoudi , 2005). The phosphorylated CREB (P-CREB) increases the expression of key target genes, including that encoding brainderived neurotrophic factor (BDNF), which, through activation of its tyrosine kinase B receptor, feeds back to regulate CREB activity, which, in turn, induces downstream structural and functional changes at the synaptic level. "
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    ABSTRACT: The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus but they differ in various aspects including reaction to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late phase long-term potentiation (L-LTP) and its signaling cascade in the DG area of the hippocampus of REM sleep deprived rats. Rats were chronically treated with caffeine (300mg/l drinking water) for four weeks after which they were sleep-deprived for 24h. The L-LTP was induced in in anesthetized rats and extracellular field potentials from the DG were recorded in vivo. The levels of L-LTP-related signaling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L-LTP magnitude, basal levels of total and phosphorylated response element-binding protein (P-CREB) in addition to those of calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented impairment of the basal levels of P- and total CREB as well as those of CaMKIV in sleep-deprived animals. Furthermore, caffeine prevented post-L-LTP sleep deprivation-induced down-regulation of P-CREB and brain-derived neurotrophic factor (BDNF) in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation-induced deficits in brain function. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · European Journal of Neuroscience
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    • "Such LTP that we called 'pharmacological' was compared to LTP induced by a single 100 Hz, 1 s train, the form that we described as 'electrical' E-LTP. From seven selected works (Winder et al., 1998; Barco et al., 2002; Woo and Nguyen, 2003; Kelleher et al., 2004; "
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    ABSTRACT: Long-term potentiation (LTP) remains the most widely accepted model for learning and memory. In accordance with this belief, the temporal differentiation of LTP into early and late phases is accepted as reflecting the differentiation of short-term and long-term memory. Moreover, during the past 30 years, protein synthesis inhibitors have been used to separate the early, protein synthesis-independent (E-LTP) phase and the late, protein synthesis-dependent (L-LTP) phase. However, the role of these proteins has not been formally identified. Additionally, several reports failed to show an effect of protein synthesis inhibitors on LTP. In this review, a detailed analysis of extensive behavioral and electrophysiological data reveals that the presumed correspondence of LTP temporal phases to memory phases is neither experimentally nor theoretically consistent. Moreover, an overview of the time courses of E-LTP in hippocampal slices reveals a wide variability ranging from <1 h to more than 5 h. The existence of all these conflictual findings should lead to a new vision of LTP. We believe that the E-LTP vs. L-LTP distinction, established with protein synthesis inhibitor studies, reflects a false dichotomy. We suggest that the duration of LTP and its dependency on protein synthesis are related to the availability of a set of proteins at synapses and not to the de novo synthesis of plasticity-related proteins. This availability is determined by protein turnover kinetics, which is regulated by previous and ongoing electrical activities and by energy store availability.
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