Strategic Timing of Glial <i>HMOX1</i> Expression Results in Either Schizophrenia-Like or Parkinsonian Behavior in Mice
Bibliographic record
Abstract
Aims: In this original research communication, we assess the impact of shifting the window of glial HMOX1 overexpression in mice from early-to-midlife to mid-to-late life, resulting in two disparate conditions modeling schizophrenia (SCZ) and Parkinson's disease (PD). Mesolimbic hyperdopaminergia is a widely accepted feature of SCZ, while nigrostriatal hypodopaminergia is the sine qua non of idiopathic PD. Although the advent of parkinsonian features in SCZ patients after treatment with antidopaminergic agents is intuitive, subtle features of parkinsonism commonly observed in young, drug-naïve schizophrenics are not. Similarly, emergent psychosis in PD subjects receiving levodopa replacement is not unusual, whereas spontaneous hallucinosis in nonmedicated persons with idiopathic PD is enigmatic. Investigations using GFAP.HMOX1 mice may shed light on these clinical paradoxes. Results: Astroglial heme oxygenase-1 (HO-1) overexpression in mice throughout embryogenesis until 6 or 12 months of age resulted in hyperdopaminergia, hyperkinesia/stereotypy ameliorated with clozapine, deficient prepulse inhibition of the acoustic startle response, reduced preference for social novelty, impaired nest building, and cognitive dysfunction reminiscent of SCZ. On the contrary, astroglial HO-1 overexpression between 8.5 and 19 months of age yielded a PD-like behavioral phenotype with hypodopaminergia, altered gait, locomotor incoordination, and reduced olfaction. Innovation: We conjecture that region-specific disparities in the susceptibility of dopaminergic and other circuitry to the trophic and degenerative influences of glial HMOX1 induction may permit the concomitant expression of mixed SCZ and PD traits within affected individuals. Conclusion: Elucidation of these converging mechanisms may (i) help better understand disease pathogenesis and (ii) identify HO-1 as a potential therapeutic target in neurodevelopmental and neurodegenerative disorders.
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How this classification was reachedexpand
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 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".