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Synaptic tagging, evaluation of memories, and the …
A role for p300 in learning and memory was established in two earlier reports. Transgenic mice with a truncated form of p300 () and mice with a forebrain-specific conditional deletion of p300 () both show impaired hippocampus-dependent memory formation. In agreement with the findings of , ), we also observed no effect of p300 inhibition on the acquisition of cued fear (). We tested the effect of a combined p300/CBP inhibitor, Lys-CoA-Tat, on the formation of fear extinction memory using a partial extinction protocol (30 CS), which elicits moderate fear extinction that is sensitive to either disruption or enhancement (, ). Contrary to previous studies demonstrating an impairment in learning and memory after p300 or CBP knockdown, we observed a significant enhancement of fear extinction memory when the mice were tested 24 h after an immediate postextinction training infusion of the combined p300/CBP inhibitor Lys-CoA-Tat (). These initial findings prompted us to explore the role of p300 in fear extinction in more detail by testing the effect of the small molecule p300 inhibitor C646 on fear extinction memory using a weak extinction protocol that does not generate a persistent extinction memory (5 CS) (). Again, we observed a significant enhancement of fear extinction memory when the mice were tested 24 h after an immediate postextinction training infusion of C646 (). Importantly, these effects were not observed if the C646 was infused 6 h after extinction training (), nor were they observed if the drug was infused into the PLPFC immediately after extinction training (). In accordance with the effect of C646 on fear extinction memory after weak extinction training, C646 also facilitated LTP within the ILPFC. Using an LTP protocol similar to one that has previously demonstrated a necessary role for the HAT CBP in hippocampal LTP (), inhibition of p300 facilitated the induction of long-lasting LTP. Indeed, a weak stimulation protocol that did not induce LTP was able to do so in the presence of the p300 inhibitor (). Together, these findings suggest an antagonistic role for p300 in the formation of fear extinction memory and in synaptic plasticity within the ILPFC.
Taking advantage of a combination of synaptic physiological methods on highly plastic embryonic neuromuscular synapses (neuromuscular junction, NMJ) and sophisticated genetics, we have proposed a novel hypothesis, “local feedback model” as a potential molecular and cellular basis of memoryformation (Yoshihara et al., 2005, 310: 858-863; Fig.
Synaptic plasticity and memory: An evaluation of the ..
Although p300 can acetylate cytoplasmic proteins (), it also interacts with transcriptional repressors such as YY1 (; ). An augmented repressor activity of YY1 by p300 coactivation at residues 170–200 was observed by , suggesting that inhibition of p300 binding to YY1 reduces the latter’s repressive function, thereby leading to increased transcriptional activity of target genes [e.g., brain-derived neurotrophic factor (BDNF)] and enhanced synaptic plasticity. In support of this hypothesis, a loss-of-function mutation of SIRT1, which acts via YY1, reduces BDNF expression, and results in impaired novel object recognition and decreased LTP in the CA1 region of the hippocampus (). Our data suggest that a potential role for a p300–YY1 interaction in the ILPFC is to constrain plasticity, whereby a reduction in p300 activity may reduce the negative regulatory influence of YY1, leading to increased BDNF expression under weak extinction training conditions. This would subsequently result in enhanced fear extinction memory and the facilitation of LTP.
Findings of the study clearly demonstrate that acute increases in cAMP levels selectively in neurons facilitate synaptic plasticity and memory, and illustrate the potential of this heterologous system to study cAMP-mediated processes in mammalian systems.
plasticity and memory: an evaluation of the hypothesis.
In our initial experiments, we tested the role of the HAT p300/CBP in the consolidation of fear extinction memory. Animals underwent cued fear conditioning on day 1 and fear extinguished in a different context 24 h later (). The combined p300/CBP inhibitor Lys-CoA-Tat or its control (DDD-CoA-Tat) was infused into the ILPFC immediately after extinction training (30 CS). Relative to retention control mice (FC-No EXT DDD-CoA-Tat), the 30 CS extinction training protocol did not lead to persistent extinction memory in extinction-trained control mice (EXT DDD-CoA-Tat). However, there was a significant reduction in freezing in mice that had received Lys-CoA-Tat immediately after extinction training (F(3,42) = 15.73; p post hoc test, FC-No EXT DDD-CoA-Tat vs EXT Lys-CoA-Tat, p ), showing enhanced extinction memory when tested 24 h after drug treatment. These findings prompted us to carry out a more detailed examination of the effect of specifically inhibiting p300 on the consolidation of fear extinction memory and synaptic plasticity in the ILPFC.
Activity of the HAT, p300, is critical for both object recognition and contextual fear memory but, interestingly, not for the acquisition of cued fear (, ). These findings suggest that p300 is preferentially involved in the regulation of gene expression associated with hippocampus-dependent learning; however, it is not yet known whether p300 is functionally involved in establishing fear extinction memory. Given the important role of the HAT family of transcriptional coactivators in regulating gene expression associated with memory formation, and the fact that the formation of fear extinction memory depends on gene expression, protein synthesis, and synaptic plasticity in the infralimbic region of the medial prefrontal cortex (ILPFC) (; ; ; ), we investigated whether p300 activity, within the ILPFC, is required for the formation of fear extinction memory. Immediately after fear extinction training, we microinfused a combined p300/cAMP-responsive element-binding protein-binding protein (CBP) inhibitor (Lys-CoA-Tat), or a small-molecule p300-specific inhibitor (C646) directly into the ILPFC, then tested fear extinction memory 24 h later. In addition, to address the role of p300 in synaptic plasticity within the ILPFC, we induced long-term potentiation (LTP) within the ILPFC in the presence or absence of C646. Contrary to previous reports demonstrating a permissive role for HAT activation in memory and LTP, our results reveal that an inhibition of p300 within the ILPFC serves to strengthen fear extinction memory and enhance synaptic plasticity.
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The synaptic plasticity and memory hypothesis: ..
Serv., 83, 199-202) to establish a new system to connect synaptic plasticityto memory, and finally identified the Fdg neuron (Flood, Iguchi et al., 2013, , 499: 83-87), which is ideal for neurophysiological analysis of classical conditioningdemonstrated by Ivan Pavlov (Fig.
Synaptic Plasticity and Memory: An Evaluation of the Hypothesis
In this study, we report two novel findings: (1) inhibition of p300 activity in the ILPFC enhances the formation of fear extinction memory in mice; and (2) p300 inhibition enhances LTP in ILPFC pyramidal neurons under conditions that do not normally evoke a persistent effect on excitatory transmission. These findings suggest that one possible function of p300 within the ILPFC is to constrain synaptic plasticity, and a reduction in the activity of this HAT is required for the formation of fear extinction memory.
Synaptic plasticity and memory: an evaluation of the hypothesis.
It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.
Brain-derived neurotrophic factor - Wikipedia
Synaptic plasticity is the ability of synapses to change, and is important to learning and memory. It is measured by long term potentiation (LTP) (Panels C-F).
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