RNA interference in hippocampus demonstrates opposing roles for CREB and PP1α in contextual and temporal long‐term memory

Peters, Marco; Bletsch, Matthew; Catapano, Ray; Zhang, X.; Tully, Tim; Bourtchouladze, Rusiko

doi:10.1111/j.1601-183x.2009.00474.x

Cited by 47 publications

(25 citation statements)

References 50 publications

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“…Peters and coworkers demonstrated that inhibition of PP-1A by RNA interference was leading to enhance contextual and temporal memory function in the mouse [36] and Haege et al linked PP-1 hippocampal mRNA expressional patterns to spatial memory in the Morris water maze [37].…”

Section: Discussionmentioning

confidence: 98%

Serine/threonine‐protein phosphatase 1 α levels are paralleling olfactory memory formation in the CD1 mouse

et al. 2011

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Although olfactory discrimination has already been studied in several mouse strains, data on protein levels linked to olfactory memory are limited. Wild mouse strains Mus musculus musculus, Mus musculus domesticus and CD1 laboratory outbred mice were tested in a conditioned odor preference task and trained to discriminate between two odors, Rose and Lemon, by pairing one odor with a sugar reward. Six hours following the final test, mice were sacrificed and olfactory bulbs (OB) were taken for gel-based proteomics analyses and immunoblotting. OB proteins were extracted, separated by 2-DE and quantified using specific software (Proteomweaver). Odor-trained mice showed a preference for the previously rewarded odor suggesting that conditioned odor preference occurred. In CD1 mice levels, one out of 482 protein spots was significantly increased in odor-trained mice as compared with the control group; it was in-gel digested by trypsin and chymotrypsin and analyzed by tandem mass spectrometry (nano-ESI-LC-MS/MS). The spot was unambiguously identified as serine/threonine-protein phosphatase PP1-α catalytic subunit (PP-1A) and differential levels observed in gel-based proteomic studies were verified by immunoblotting. PP-1A is a key signalling element in synaptic plasticity and memory processes and is herein shown to be paralleling olfactory discrimination representing olfactory memory.

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Section: Discussionmentioning

confidence: 98%

Serine/threonine‐protein phosphatase 1 α levels are paralleling olfactory memory formation in the CD1 mouse

et al. 2011

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“…The importance of CREB for memory has now been demonstrated through bidirectional manipulation of CREB function 23,24 . Researchers have used a variety of methods to negatively modulate CREB, including the knockdown of CREB (specifically α/δ isoforms), antisense oligodeoxynucleotide-mediated CREB disruption, RNA interference, and targeted genetic mutation 23,25–27 . These manipulations invariably lead to memory deficits.…”

Section: The Role Of the Transcription Factor Creb In Memorymentioning

confidence: 99%

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

et al. 2018

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The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have > 10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function.

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“…In neurons, activation of protein kinase A (PKA) leads to CREB phosphorylation and consequent activation (Matsushita et al, 2001). Some forms of late LTP and LTM require activation of CREB (Kida, 2012; Peters et al, 2009; Pittenger et al, 2002) and co-activation of CBP (Korzus et al, 2004; Levenson et al, 2004). We explored whether our previous model describing LTP induction (Smolen et al, 2006), extended to include CBP and acetylation, could: a) simulate the impaired LTP seen in rodent models for RTS, b) suggest modulation of specific biochemical parameters as potential targets to rescue the deficit in LTP, c) identify pairs of parameters that are plausible drug targets and, when concurrently varied, rescue the deficit in LTP, and d) predict regions of synergism associated with concurrent adjustments to these parameter pairs.…”

Section: Introductionmentioning

confidence: 99%

Simulations suggest pharmacological methods for rescuing long-term potentiation

Smolen

Baxter

Byrne

2014

Journal of Theoretical Biology

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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.

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RNA interference in hippocampus demonstrates opposing roles for CREB and PP1α in contextual and temporal long‐term memory

Cited by 47 publications

References 50 publications

Serine/threonine‐protein phosphatase 1 α levels are paralleling olfactory memory formation in the CD1 mouse

Serine/threonine‐protein phosphatase 1 α levels are paralleling olfactory memory formation in the CD1 mouse

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

Simulations suggest pharmacological methods for rescuing long-term potentiation

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