This shows the power of cell-type-specific RNA profiling to uncover hidden vulnerabilities. EPAC2 inhibition could be a game-changer for FXS.

And it worked.
✨ Restored cortical circuit function
✨ Ameliorated sensory behavioral phenotypes
Targeting EPAC2 rescued key Fragile X features — offering a new therapeutic path forward! 🔥

EPAC2, a cAMP-activated synaptic regulator, became our focus. We tested whether blocking EPAC2 could fix the circuit deficits. Using ESI-05, a selective EPAC2 inhibitor, we treated Fmr1 KO mice. 🧪

Of hundreds of differentially expressed genes (DEGs), only 194 were shared across both neuron types. Amazingly, just one gene — Rapgef4 (Epac2) — was a brain-enriched ASD risk gene and a direct FMRP target. 🧬

Using cell type-specific RNA-seq in Fmr1 knockout (KO) mice, we found opposite effects: genes were upregulated in excitatory neurons but downregulated in PV inhibitory neurons. Dramatic shifts in brain wiring.