Characterization of translational regulation during long-term facilitation in «Aplysia»
Notice bibliographique
Résumé
It is well established that the new macromolecular synthesis required for both long-term synaptic plasticity and long-term memory involves not only transcriptional regulation but translational regulation as well. Target of rapamycin (TOR) complex 1 (TORC1), a key regulator of translation, has been implicated in numerous forms of long-term synaptic plasticity and memory. A powerful model system for studying the changes underlying memory formation is synaptic facilitation at sensory-to-motor neuron synapses in the sea slug, Aplysia, as both short- and long-term forms of this type of synaptic plasticity have been shown to contribute to short- and long-term memory, respectively, for behavioural sensitization of the gill-/siphon-withdrawal reflex. Here, we have begun to characterize the nature of the signalling pathways through which translation is regulated during long-term facilitation (LTF). In one study, we expressed dominant negative forms of the two known immediate downstream effectors of TORC1: eukaryotic initiation factor 4E (eIF4E) binding protein (4E-BP) and ribosomal protein S6 kinase (S6K), and examined the effects of specifically disrupting each pathway on a phase of LTF known to require TORC1 signalling, 24-hr LTF. A translational reporter construct was also used to examine the effects of the two dominant negatives on TORC1-mediated stimulation of general translation. 24-hr LTF was found to require S6K, but not 4E-BP, signalling. As neither dominant negative construct blocked TORC1-mediated increases in general translation, the requirement for S6K signalling during 24-hr LTF likely reflects a requirement for translational upregulation of a specific transcript or subset of transcripts, not reported by the general translational reporter construct. This study has begun to narrow down the TORC1 pathways involved in LTF, specifically, which will help identify the transcripts whose translational upregulation is required for this form of long-term synaptic plasticity and will shed light on the important processes engaged by TORC1 during memory formation, in general.In a second study, we sought to further hone in on the requisite TORC1 signalling pathways during 24-hr LTF by first characterizing TORC1-mediated regulation of eukaryotic elongation factor 2 (eEF2), one of the downstream effectors of S6K in other systems. To this end, using an antibody that specifically recognizes eEF2 kinase (eEF2K) phosphorylated at a putative S6K phosphorylation site, we first demonstrate that in Aplysia, as in other systems, S6K mediates phosphorylation of eEF2K. Expression of a mutant form of eEF2K that cannot be phosphorylated at this site blocked a serotonin- (a.k.a. 5-hydroxytryptamine- (5-HT-)) induced decrease in eEF2 phosphorylation in isolated neurites, indicating that the effect of S6K on eEF2 phosphorylation is also conserved. Surprisingly, within the sensory neuron (SN) soma, 5-HT treatment resulted in a decrease in eEF2K phosphorylation at the S6K site and a concomitant increase in eEF2 phosphorylation, indicating that 5-HT engages a second parallel pathway that opposes the effects of S6K activation. Finally, overexpression of eEF2K caused a similar increase in eEF2 phosphorylation and resulted in a specific increase in translation of a reporter of general translation in the face of inhibited internal-ribosome-entry-site- (IRES-) dependent translation. This last result extends, to invertebrates, the previous, seemingly paradoxical, finding that inhibition of translational elongation can stimulate the translation of certain transcripts. As this novel mechanism of translational regulation has been implicated in mammalian forms of long-term synaptic plasticity, 5-HT-induced somatic decreases in eEF2K phosphorylation and subsequent increases in eEF2 phosphorylation may engage a mechanism of translational regulation fundamental to the establishment of long-term memory.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».