Glutamatergic signaling in oligodendrocyte progenitors
Bibliographic record
Abstract
The excitatory neurotransmitter, glutamate, plays an important role in synaptic transmission, brain development and plasticity as well as excitotoxicity. The biological functions of glutamate in neurons are mediated by ion channel-gated or G-protein-coupled receptors that are also located on glial cells, including oligodendrocytes. However, the functions of glutamate receptors in oligodendrocytes and their progenitors remain unknown. The objective of work presented in this thesis was to characterize the effects of glutamate on oligodendrocyte progenitors and the intracellular signaling pathways involved in mediating these effects. Glutamate caused a time- and concentration-dependent increase in inositol 1,4,5-trisphosphate (IP3) levels in oligodendrocyte progenitors. Using selective antagonists, we demonstrated that the effect of glutamate was mediated by an ionotropic receptor of the AMPA subtype. Glutamate-stimulated phospholipase C (PLC) activation was triggered by Ca2+ influx through AMPA receptors as well as through voltage-gated Ca2+ channels and the Na+/Ca2+ exchangers operating in the reverse mode. Furthermore, the AMPA receptor agonists, AMPA and kainate, increased phosphorylation of the extracellular signal-regulated kinase (ERK) subtype of the mitogen-activated protein kinase family. ERK activation required extracellular Ca2+ and activation of PLC and protein kinase C (PKC). The involvement of PKC was further supported by the observed kainate-induced translocation of PKC, measured by PDBu binding. Interestingly, a phosphatidylinositol-3-kinase and a pertussis toxin-sensitive G-protein are part of the signaling cascade leading to ERK activation. In addition, glutamate and kainate caused an increase in c-fos expression. Both extracellular Ca2+ and PKC, which are upstream activators of ERK, were required for c-fos gene expression. Blocking the ERK pathway reduced kainate-induced c-fos expression, indicating that ERK was involved in transmitting signaling events to the nucleus. In addition, the effect of glutamate on the development of oligodendrocyte progenitors was examined. We found that glutamate, at the non-toxic concentrations, inhibited the proliferation of oligodendrocyte progenitors. Excessive activation of AMPA receptors, achieved pharmacologically by inhibiting receptor desensitization with cyclothiazide, was toxic to oligodendrocyte progenitors. Ensuing cell death displayed several features characteristic of apoptosis, including DNA fragmentation, chromatin condensation and caspase-3 activation. Underlying molecular mechanisms implicated in excitotoxicity included massive Ca2+ influx, intracellular glutathione depletion and activation of c-Jun N-terminal kinase and calpain. Furthermore, the antioxidant, N-acetylcysteine, prevented cell death by maintaining intracellular glutathione levels. Collectively, our findings show that glutamate, acting via the AMPA receptor, initiates multiple signal transduction pathways that may be involved in the growth and/or survival of oligodendrocytes.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".