Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target
Bibliographic record
Abstract
Symptoms of fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell-type-specific mRNA sequencing to profile molecular alterations in cortical excitatory (Camk2) and inhibitory (Pvalb) neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. We uncovered significant genotype-by-cell type interactions for differential gene expression in Camk2a and Pvalb translatomes, and, strikingly, the underlying signaling pathways were often altered in opposite directions. Among the 184 differentially expressed genes that were concordantly dysregulated across both cell types, only Rapgef4 (a.k.a., exchange protein direftly activated by cAMP 2 [Epac2]; upregulated in Fmr1 KO) was also a fragile X messenger ribonucleoprotein (FMRP) target, brain-enriched, and associated with neurodevelopmental disorders. Treatment of Fmr1 KO mice with a specific EPAC2 antagonist restored cortical circuit function and ameliorated multiple behavioral phenotypes. Thus, EPAC2 should be considered a potential therapeutic target for FXS.
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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".