Olanzapine-induced DNA methylation in the hippocampus and cerebellum in genes mapped to human 22q11 and implicated in schizophrenia
Bibliographic record
Abstract
BACKGROUND: Although there is indirect evidence that the effects of antipsychotic drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects by epigenetic modulation. Here, we tested the effect of an antipsychotic, olanzapine, on the DNA methylation status of genes following chronic treatment using rat-specific methylation arrays. METHODS: Forty-eight hours after the last dose of olanzapine/vehicle, rats were habituated to an open-field activity-monitoring chamber for 30 min to verify whether stress-induced locomotor activity was reduced in olanzapine-treated rats. To test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of 49 genes mapped to human 22q11 and implicated in schizophrenia. Genomic DNA isolated from the cerebellum, hippocampus, and liver of olanzapine-treated (n=2) and control (n=2) rats were analyzed using rat-specific methylation arrays. RESULTS: Significantly reduced locomotor activity of olanzapine-treated rats confirmed the therapeutic efficacy of the drug administered. The effects of olanzapine have been shown through significantly increased (P<0.01) DNA methylation of genes affecting several networks mainly (i) neurological disease, inflammatory disease, and inflammatory response and (ii) cancer, cell death and survival, tumor morphology. Also, proline degradation and L-DOPA degradation were affected by olanzapine-induced DNA methylation. Further, from a set of genes in the 22q11.2 microdeletions that has been implicated previously in psychosis, 29 genes showed increased methylation following olanzapine treatment. CONCLUSION: The results showed that considerable number of genes (34/49) mapped to human 22q11 and implicated in schizophrenia were affected by olanzapine-induced DNA methylation. The results suggest that DNA methylation may play a role in the therapeutic efficacy of olanzapine.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".