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: 33.12). 04/2002; 108(5):689-703. DOI: 10.1016/S0092-8674(02)00657-8
Source: PubMed

ABSTRACT 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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Available from: Angel Barco, Aug 19, 2015
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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.
    Reviews in the neurosciences 05/2015; DOI:10.1515/revneuro-2014-0072 · 3.31 Impact Factor
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    • "These pathways are established as essential for LTP. PKA phosphorylation of an unspecified substrate is necessary to set a synaptic tag required for synaptic " capture " of proteins necessary for late LTP (Barco et al., 2002; Frey and Morris, 1997; Redondo and Morris, 2011). This PKA-sensitive synaptic tag is denoted Tag-2 (Fig. 1). "
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    ABSTRACT: Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie the induction or maintenance of synaptic plasticity. For example, Rubinstein-Taybi syndrome (RTS) is due to a mutation in cbp, encoding the histone acetyltransferase CREB-binding protein (CBP). CBP is a transcriptional co-activator for CREB, and induction of CREB-dependent transcription plays a key role in long-term memory (LTM). In animal models of RTS, mutations of cbp impair LTM and late-phase long-term potentiation (LTP). As a step toward exploring plausible intervention strategies to rescue the deficits in LTP, we extended our previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by model parameter changes, and many increased LTP. However no parameter variation consistent with a biochemical effect of a known drug class fully restored LTP. Thus we examined paired parameter variations consistent with effects of known drugs. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored normal LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated the effects of a phosphodiesterase inhibitor and an acetylase activator was similarly effective. For both pairs strong additive synergism was present. The effect of the combination was greater than the summed effect of the separate parameter changes. These results suggest that promoting histone acetylation while simultaneously slowing the degradation of cAMP may constitute a promising strategy for restoring deficits in LTP that may be associated with learning deficits in RTS. More generally these results illustrate how the strategy of combining modeling and empirical studies may provide insights into the design of effective therapies for improving long-term synaptic plasticity and learning associated with cognitive disorders.
    Journal of Theoretical Biology 07/2014; 360. DOI:10.1016/j.jtbi.2014.07.006 · 2.30 Impact Factor
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    • "Thus, activation of either receptor will lead to a phosphorylation processes, albeit possibly of different proteins. The two signaling cascades converge ultimately on a common pathway involving the transcription factor, CREB (cAMP response element-binding protein) that supports long-term synaptic plasticity in the hippocampus [45]. "
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    ABSTRACT: Memory consolidation is the process by which recently acquired information becomes stable and is modulated by different neurotransmitters depending on the structure involved and the nature of the memory. Here we evaluate the participation of both D1 and D5 dopamine receptors in the CA1 region of the hippocampus in the consolidation of the memory of two different tasks, object recognition (OR) and inhibitory avoidance (IA). For this, male rats with infusion cannulae stereotaxically implanted in the CA1 region of the dorsal hippocampus were trained in an OR task involving exposure to two different objects, or in a one-trial step-down IA task. At different times after the training, rats some of the animals received intrahippocampal infusions of the D1-family receptor antagonist SCH-23390. In a test session carried out 24h later, the animals that received infusions immediately or 60min but not 180min after the training showed impaired long-term memory. Since D1- and D5-subtypes engage different signaling pathways involving cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), respectively, we assessed whether they participate distinctively in consolidation. The animals that received intra-CA1 infusions of the PKA inhibitor, Rp-cAMP, or the PKC inhibitor, Gö6976, immediately after OR or IA training had a long-term memory impairment and the amnesic effect caused by SCH-23390 was reversed when co-infused with activators of PKA (8Br-cAMP) or PKC (PMA). These results indicate that both D1 and D5 dopamine receptors are required in the CA1 region of the hippocampus for consolidation of the two tasks. This supports the notion of a commonality of consolidation mechanisms across tasks.
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