Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol

Liu, Rong‐Yu; Neveu, Curtis L; Smolen, Paul; Cleary, Leonard J.; Byrne, John H.

doi:10.1101/lm.044834.116

Cited by 9 publications

(21 citation statements)

References 61 publications

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“…L-LTP in dentate gyrus has been observed to last for at least 1 year (Abraham et al 2002). LTF persists for at least 1 week, and depends on protein synthesis as well as transcription (Montarolo et al 1986;Bailey et al 1992;Miniaci et al 2008;Hu et al 2011;Liu et al 2017).…”

Section: Introductionmentioning

confidence: 99%

How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory

Smolen¹,

Baxter²,

Byrne³

2019

Learn. Mem.

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With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding. Such feedback may occur within signal-transduction cascades and/or the regulation of translation, and it may occur within specific subcellular compartments or within neuronal networks. Not surprisingly, numerous positive feedback loops have been proposed. Some posited loops operate at the level of biochemical signal transduction cascades, such as persistent activation of Ca 2+ /calmodulin kinase II (CaMKII) or protein kinase M ζ. Another level consists of feedback loops involving transcriptional, epigenetic and translational pathways, and autocrine actions of growth factors such as BDNF. Finally, at the neuronal network level, recurrent reactivation of cell assemblies encoding memories is likely to be essential for late maintenance of memory. These levels are not isolated, but linked by shared components of feedback loops. Here, we review characteristics of some commonly discussed feedback loops proposed to underlie the maintenance of memory and long-term synaptic plasticity, assess evidence for and against their necessity, and suggest experiments that could further delineate the dynamics of these feedback loops.We also discuss crosstalk between proposed loops, and ways in which such interaction can facilitate the rapidity and robustness of memory formation and storage. Smolen et al. 3

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Section: Introductionmentioning

confidence: 99%

How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory

Smolen¹,

Baxter²,

Byrne³

2019

Learn. Mem.

Self Cite

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“…In another modelling work, Zhang et al (2012) , building on the model by Pettigrew et al (2005) ( Pettigrew et al, 2005 ; Zhang et al, 2012 ), studied the effects of 5-HT on PKA-ERK interactions to enhance long-term facilitation of synapses. In a similar vein, Zhou et al (2014) modelled both PKA and PKC signalling to show that PKC was sufficient for short-term facilitation of synapses, and that cooperation among the signalling cascades could potentially contribute to the enhancement of learning and memory, which had recently been validated experimentally ( Liu et al, 2017 ; Zhou et al, 2014 ). These results may have implications in AD, given the latter's deterioration in learning and memory.…”

Section: Towards Multiscale Computational Modelling Of Serotonergic Smentioning

confidence: 92%

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

et al. 2020

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Alzheimer's disease (AD) is an age-specific neurodegenerative disease that compromises cognitive functioning and impacts the quality of life of an individual. Pathologically, AD is characterised by abnormal accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein. Despite research advances over the last few decades, there is currently still no cure for AD. Although, medications are available to control some behavioural symptoms and slow the disease's progression, most prescribed medications are based on cholinesterase inhibitors. Over the last decade, there has been increased attention towards novel drugs, targeting alternative neurotransmitter pathways, particularly those targeting serotonergic (5-HT) system. In this review, we focused on 5-HT receptor (5-HTR) mediated signalling and drugs that target these receptors. These pathways regulate key proteins and kinases such as GSK-3 that are associated with abnormal levels of Aβ and tau in AD. We then review computational studies related to 5-HT signalling pathways with the potential for providing deeper understanding of AD pathologies. In particular, we suggest that multiscale and multilevel modelling approaches could potentially provide new insights into AD mechanisms, and towards discovering novel 5-HTR based therapeutic targets.

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“…For immunocytochemistry, SNs were isolated from the same animal in each experimental repetition. Therefore, the paired t-test (between two groups), or repeated measures one-way (RM) ANOVA was used on raw data, followed by the post hoc Student-Newman-Keuls method (SNK) for multiple comparisons analysis 13,14,16,21 . For measuring multiple time points of pRSK after 5-HT ( Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Intriguingly, the immunoreactivities for pERK and pRSK in Aplysia are mainly located in the cytoplasm. However, minor proportions of pERK 21,[28][29][30] and pRSK (Figs. 2 and 3) are detected in the nucleus.…”

Section: Revised Model Of Aplysia Ltf This Study Also Extends the Unmentioning

confidence: 95%

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Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

Liu¹,

Zhang²,

Smolen³

et al. 2020

Sci Rep

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Multiple kinases converge on the transcription factor cAMP response element-binding protein (CREB) to enhance the expression of proteins essential for long-term synaptic plasticity and memory. The p90 ribosomal S6 kinase (RSK) is one of these kinases, although its role is poorly understood. The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the role of RSK in long-term synaptic facilitation (LTF) and long-term enhancement of neuronal excitability (LTEE), two correlates of long-term memory (LTM). Inhibition of RSK expression or RSK activity both significantly reduced CREB1 phosphorylation, LTF, and LTEE, suggesting RSK is required for learningrelated synaptic plasticity and enhancement in neuronal excitability. In addition, knock down of RSK by RNAi in Aplysia sensory neurons impairs LTF, suggesting that this may be a useful single-cell system to study aspects of defective synaptic plasticity in Coffin-Lowry Syndrome (CLS), a cognitive disorder that is caused by mutations in rsk2 and associated with deficits in learning and memory. We found that the impairments in LTF and LTEE can be rescued by a computationally designed spaced training protocol, which was previously demonstrated to augment normal LTF and LTM. In mammals, gene deletion studies have shown an essential role for the rsk2 gene in cognitive functions 1. In several animal models, the p90 isoform of RSK, expressed from rsk2, phosphorylates (i.e., activates) CREB after activation by the ERK isoform of MAP kinase (MAPK) 2-6. Coffin-Lowry Syndrome (CLS) is caused by X-linked mutations in rsk2, and is associated with human intellectual disability and skeletal abnormalities 7. A mouse rsk2-null model is deficient in fear memory consolidation and stimulus-induced CREB phosphorylation 1,8. CREB-mediated transcription is required for memory formation in vertebrates and invertebrates. In mammalian systems, many of the signaling pathways that lead to phosphorylation of CREB have been well characterized, including the cAMP/PKA pathway and the Ras/ERK pathway 9. However, the potential ERK/RSK/CREB pathway has received little attention as a potential contributor to synaptic plasticity, including long-term potentiation (LTP) and long-term synaptic facilitation (LTF), and also to long-term enhancement of neuronal excitability (LTEE). LTP, LTF, and LTEE are known correlates of long-term memory (LTM). To our knowledge, no study so far has examined the effects of RSK inhibitors on synaptic plasticity or excitability. One study examined the role of RSK2 in LTP using a RSK2 mutant mouse 8. A negative result was reported-LTP was normal in the mutant. The negative result may be explained by the effects of RSK activation not being expressed during the period of observation (120 minutes), or a different isoform of RSK may have compensated for the mutant. Consequently, the role of RSK in long-term synaptic plasticity and enhancement of excitability remains unsettled. The present study exploited advantages of the Aplysia sen...

show abstract

Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol

Cited by 9 publications

References 61 publications

How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory

How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

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