Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Abstract Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist with recovery and repair, prolonged microglial pro‐inflammatory responses are known to exacerbate neurodegenerative processes. Yet, detrimental outcomes of extended microglial activation are counterbalanced by beneficial outcomes including phagocytosis and release of trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a key signaling hub driving pro‐inflammatory microglia responses, but the signaling pathway maintaining PARP‐1 activation remains elusive. While best understood for its role in promoting DNA repair, our group has shown that PARP‐1 activity can be stimulated via Ca 2+ influx‐dependent ERK1/2‐mediated phosphorylation. However, to date, the route of Ca 2+ entry responsible for stimulating PARP‐1 has not been identified. A likely candidate is via Ca 2+ ‐permeable transient receptor potential melastatin 2 (TRPM2) channels activated downstream of PARP‐1 in a cascade that involves ADP‐ribose (ADPR) production by poly(ADP‐ribose) glycohydrolase (PARG). Here we demonstrate that NMDA receptor (NMDAR) stimulation in primary cultured microglia induces their proliferation, morphological activation and release of pro‐inflammatory mediators. These responses were contingent on the recruitment of PARP‐1, PARG and Ca 2+ permeable TRPM2 channels. Furthermore, we show that Ca 2+ influx is necessary to activate PARP‐1/TRPM2 signaling, in an ERK1/2‐dependent, but DNA damage independent, manner. Our findings, showing that PARP‐1/TRPM2 mediate the pro‐inflammatory effects of NMDAR stimulation, provides a unifying mechanism linking elevated glutamate levels to chronic neuroinflammation.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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 | 0.001 |
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 it