GluR2 endocytosis-dependent protein degradation in the amygdala mediates memory updating

Ferrara, Nicole C.; Jarome, Timothy J.; Cullen, Patrick K.; Orsi, Sabrina A.; Kwapis, Janine L.; Trask, Sydney; Pullins, Shane E.; Helmstetter, Fred J.

doi:10.1038/s41598-019-41526-1

Cited by 43 publications

(45 citation statements)

References 40 publications

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“…Consistent with this, when memory is retrieved, CI-AMPARs are transiently replaced by CP-AMPARs, triggering the destabilization process [64,98]. Notably, blocking either GluA2 endocytosis or protein degradation in the amygdala can prevent reconsolidation-dependent fear memory updating [64]. As blocking GluA2 endocytosis also prevented retrieval-induced increases in a marker of protein degradation, this work strongly suggests that GluA2 endocytosis is upstream of protein degradation.…”

Section: Molecular Mechanisms Of Memory Destabilizationsupporting

confidence: 60%

“…This inherent instability of the CP-AMPARs is thought to allow for synaptic malleability, whereas CI-AMPARs contribute to basal neurotransmission and synaptic stability [22,92]. Consistent with this, when memory is retrieved, CI-AMPARs are transiently replaced by CP-AMPARs, triggering the destabilization process [64,98]. Notably, blocking either GluA2 endocytosis or protein degradation in the amygdala can prevent reconsolidation-dependent fear memory updating [64].…”

Section: Molecular Mechanisms Of Memory Destabilizationmentioning

confidence: 90%

“…Did not prevent pharmacological-induced amnesia [99] Prevented updating [31,42,92] Synthetic GluA2 causing inhibition [36,98] Pharmacological inhibition of GluA2 [64] Performed multiple retrieval events Affected GluA1 phosphorylation [72,80] Pre-exposed animal to retrieval context to prevent memory updating…”

Section: Pharmacological Inhibitionmentioning

confidence: 99%

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Molecular Mechanisms of Reconsolidation-Dependent Memory Updating

Bellfy

Kwapis

2020

IJMS

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Memory is not a stable record of experience, but instead is an ongoing process that allows existing memories to be modified with new information through a reconsolidation-dependent updating process. For a previously stable memory to be updated, the memory must first become labile through a process called destabilization. Destabilization is a protein degradation-dependent process that occurs when new information is presented. Following destabilization, a memory becomes stable again through a protein synthesis-dependent process called restabilization. Much work remains to fully characterize the mechanisms that underlie both destabilization and subsequent restabilization, however. In this article, we briefly review the discovery of reconsolidation as a potential mechanism for memory updating. We then discuss the behavioral paradigms that have been used to identify the molecular mechanisms of reconsolidation-dependent memory updating. Finally, we outline what is known about the molecular mechanisms that support the memory updating process. Understanding the molecular mechanisms underlying reconsolidation-dependent memory updating is an important step toward leveraging this process in a therapeutic setting to modify maladaptive memories and to improve memory when it fails.

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Section: Molecular Mechanisms Of Memory Destabilizationsupporting

confidence: 60%

Section: Molecular Mechanisms Of Memory Destabilizationmentioning

confidence: 90%

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Molecular Mechanisms of Reconsolidation-Dependent Memory Updating

Bellfy

Kwapis

2020

IJMS

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“…It has been proposed that memory retrieval and reactivation mechanisms may be partially inhibited by ZIP. For instance, the AMPA receptor GluR2A subunit trafficking into synapses is induced by memory retrieval and is necessary for memory reconsolidation [47][48][49] . Since ZIP's action is correlated with an inhibition of GluR2A trafficking, this drug could have impaired the memory reactivation and, therefore, the reconsolidation process was not sufficiently induced, which in turn prevented the action of ZIP to occur.…”

Section: Discussionmentioning

confidence: 99%

Role of prelimbic cortex PKC and PKMζ in fear memory reconsolidation and persistence following reactivation

Silva

Raymundi

Bertoglio

et al. 2020

Sci Rep

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the persistence of newly acquired memories is supported by the activity of pKMζ, an atypical isoform of protein kinase c (pKc). Whether the activity of conventional and atypical pKc isoforms contributes to reactivated memories to persist is still unknown. Similarly, whether memory reactivation is a prerequisite for interventions to be able to change memory persistence is scarcely investigated. Based on the above, we examined the role of conventional and atypical pKc isoforms in the prelimbic cortex in reconsolidation and persistence of a reactivated contextual fear memory in male Wistar rats. it is shown that (i) inhibiting the pKc activity with chelerythrine or the pKMζ activity with Zip impaired the persistence of a reactivated memory for at least 21 days; (ii) ZIP given immediately after memory reactivation affected neither the reconsolidation nor the persistence process. In contrast, when given 1 h later, it impaired the memory persistence; (iii) chelerythrine given immediately after memory reactivation impaired the reconsolidation; (iv) omitting memory reactivation prevented the chelerythrine-and ZIP-induced effects: (v) the ZIP action is independent of the time elapsed between its administration and the initial memory test. the results indicate that prelimbic cortex pKc and pKMζ are involved in memory reconsolidation and persistence.

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“…( Figure 3C, 3D, Figure EV 3A and 3B ). We speculated that the observed reduction in the FUNCAT intensity was because of protein degradation [47][48][49]. To investigate this, we repeated NMDA stimulation for 2 minutes in the presence of MG132 (1µM), a 26s proteasome inhibitor that significantly improved the FUNCAT intensity compared to cultures treated with NMDA alone.…”

Section: Resultsmentioning

confidence: 99%

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

Dastidar

Sharma

Chakraborty

et al. 2019

Preprint

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21Neuronal activity is responsible for disproportionally large consumption of energy by 22 the brain. However, little is known about the processes within neurons responsible for 23 such abundant ATP outlay. Here we provide evidence that major fraction of ATP 24 consumed on glutamate stimulation is due to activation of global de-novo protein 25 synthesis mediated by group I mGluRs in cultured cortical neurons. We found mGluR 26 and NMDAR stimulation impacts translation with distinct kinetics; while mGluR lead to 27 rapid and sustained translation activation as measured by eEF2 phosphorylation and 28 metabolic labeling, NMDAR stimulation induced a robust translation inhibition. Our 29 observations established an inverse correlation between the kinetics of translation and 30 change in ATP level for both receptors. We observed an immediate mGluR mediated 31 reduction in neuronal ATP level while NMDA lead to a delayed (≥15 mins) protein 32 synthesis dependent ATP expenditure demonstrating a possibility for NMDAR dependent 33 delayed translation activation. Interestingly, we identified that AMP activated protein 34 kinase (AMPK) has a central role in regulating downstream effects of both mGluR and 35 NMDAR. AMPK activity was reduced on mGluR stimulation even under low ATP levels 36 while there was a rapid increase in AMPK activity on NMDAR stimulation. Perturbing 37 AMPK function prior to either stimulation led to a complete loss of stimulation specific 38 effects on eEF2 phosphorylation and global translation. Our observation therefore 39 established a pivotal role for AMPK-eEF2 signaling axis on receptor specific regulation 40 of global translation.41 42 109 dependent reduction was absent in presence of protein synthesis inhibitors anisomycin 110 (25μM) or cycloheximide (100μg/ml) (Figure 1B) while drugs themselves had no 111 significnat impact on the ATP/(ATP+ADP) ratio. These observations suggest a large 112 increase in protein synthesis on stimulation, responsible for consuming signifcant 113 fraction of neuronal ATP. The identical effects of both anisomycin and cycloheximide 114 negates the possibility of these observations due to non-specific effects of these drugs. 115 Further, to understand the contributions from individual glutamate receptors, we 116 repeated glutamate stimulation inhibiting either ionotropic NMDA and AMPA receptors 117 with a cocktail of D-AP5 (25μM) + CNQX (40μM) (referred to as inotropic glutamate 118 receptor (iGluR) blocker cocktail hereafter) or inhibiting mGluRs with MPEP (10μM). Co-119 stimulation with iGluR blocker cocktail led to significant reduction in ATP/(ATP+ADP) 120 ratio similar to glutamate alone while stimulation along with MPEP abolished the 121 glutamate mediated reduction significantly (Figure 1C). These results therefore, 122 indicate that the observed reduction in ATP on glutamate stimulation is majorly due to 123 mGluR activity with minimal contributions from the iGluRs. Furthermore, Stimulation 124 in presence iGluR blocker cocktail along with protein synthesis inhib...

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GluR2 endocytosis-dependent protein degradation in the amygdala mediates memory updating

Cited by 43 publications

References 40 publications

Molecular Mechanisms of Reconsolidation-Dependent Memory Updating

Molecular Mechanisms of Reconsolidation-Dependent Memory Updating

Role of prelimbic cortex PKC and PKMζ in fear memory reconsolidation and persistence following reactivation

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

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