Ablation of optineurin impairs metabotropic glutamate receptor 5 signaling in mouse hippocampus
Bibliographic record
Abstract
Optineurin (OPTN) is a ubiquitously expressed autophagy adaptor that forms a functional interactome with Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gα q/11 protein receptor family. OPTN attenuates mGluR1 coupling to phospholipase Cβ (PLCβ) and subsequent inositol trisphosphate (IP3) formation in response to agonist stimulation. We have also demonstrated that pathological mGluR5 signaling impairs autophagic machinery via GSK3β/ZBTB16 pathway in both Alzheimer's and Huntington's disease mouse models. In this study, we investigated whether mGluR5 signaling is regulated in an OPTN‐dependent manner. We knocked out Optn gene in STHdh Q7/Q7 striatal cells using CRISPR/Cas9 approach and employed OPTN null mice to probe the impact of OPTN loss on mGluR5 canonical and autophagic signaling. We show that OPTN deletion enhances Ca 2+ mobilization following mGluR5 activation in STHdh Q7/Q7 cells and impairs mGluR5‐mediated ERK1/2 phosphorylation in both STHdh Q7/Q7 cells and acute hippocampal slices. In addition, OPTN loss enhanced basal GSK3β activity and increased the breakdown of ZBTB16 in STHdh Q7/Q7 cells, and abolished mGluR5‐mediated inactivation of GSK3β/ZBTB16 pathway in hippocampal slices. OPTN deletion also increased the expression levels of autophagy adaptor P62 in hippocampal slices, an effect that was reversed by mGluR5 antagonism. Overall, the data suggest that mGluR5 and OPTN crosstalk is essential for mGluR5 signaling and therefore can potentially contribute to the pathophysiology of neurodegenerative diseases.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".