Cortical GABAergic Neuron Dysregulation in Schizophrenia Is Age Dependent
Why this work is in the frame
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Bibliographic record
Abstract
Background: Cortical GABAergic (gamma-aminobutyric acidergic) neuron dysregulation is implicated in schizophrenia (SCZ), but it remains unclear whether these changes are due to altered cell proportions or per-cell changes in messenger RNA (mRNA) expression. Methods: We analyzed 14 bulk and cell type-specific RNA sequencing (RNA-seq) datasets from 1408 individuals (672 SCZ cases, 736 controls) across 3 neocortical regions. We deconvolved GABAergic cell-subtype proportions from bulk RNA-seq and benchmarked them against single-nucleus RNA-seq and stereological densities from matched donors. We assessed SCZ- and age-associated changes in cell proportions and per-cell gene expression. Results: SCZ was associated with altered proportions of neocortical parvalbumin (PVALB) and somatostatin (SST) cells, depending on the subject's age at death. Younger SCZ cases (age < 70 years) showed reduced PVALB and SST cell proportions, while older cases showed unchanged or increased proportions compared with controls. Earlier-onset SCZ, associated with more severe clinical symptoms, was linked to greater reductions in these cell types. Additionally, there was robust evidence for reduced per-cell SST and vasoactive intestinal peptide mRNA among younger cases with SCZ. Conclusions: These findings suggest that SCZ is associated with complex, age-dependent alterations in GABAergic neurons, particularly affecting PVALB and SST cells. Our study underscores the importance of age-stratified analyses in SCZ, suggesting that distinct pathological processes underlie GABAergic neuron dysregulation across different age and symptom-severity groups and warranting tailored therapeutic approaches.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.001 |
| 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 it