Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia
Bibliographic record
Abstract
Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.
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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".