Characterization of translational regulation during long-term facilitation in «Aplysia»
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".