Emergent glutamate & dopamine dysfunction in VPS35(D620N) knock-in mice and rapid reversal by LRRK2 inhibition
Bibliographic record
Abstract
The D620N variant in Vacuolar Protein Sorting 35 (VPS35) causes autosomal-dominant, late-onset Parkinson's disease. VPS35 is a core subunit of the retromer complex that canonically recycles transmembrane cargo from sorting endosomes. Although retromer cargoes include many synaptic proteins, VPS35's neuronal functions are poorly understood. To investigate the consequences of the Parkinson's mutation, striatal neurotransmission was assessed in 1- to 6-month-old VPS35 D620N knock-in (VKI) mice. Spontaneous and optogenetically-evoked corticostriatal glutamate transmission was increased in VKI spiny projection neurons by 6 months and was unaffected by acute leucine-rich repeat kinase 2 (LRRK2) inhibition. Total striatal glutamate release by iGluSnFR imaging was similar to wild-type. dLight imaging revealed robust increases in VKI striatal dopamine release by 6 months, which were reversed with acute LRRK2 kinase inhibition. We conclude that increased striatal neurotransmission in VKI mice progressively emerges in young-adulthood, and that dopamine dysfunction is likely the result of sustained, rapidly-reversible, LRRK2 hyperactivity.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".