Antidepressants promote developmental-like plasticity through remodeling of extracellular matrix

Selective serotonin reuptake inhibitors like Fluoxetine (Flx) are widely used to treat mood and anxiety disorders. Despite decades of use, the molecular logic by which they modulate stress-related behaviors remain poorly understood. Here we show that Flx reactivates a developmental-like plasticity program in the dentate gyrus (DG) by remodeling the extracellular matrix (ECM). Single-nucleus RNA sequencing of the hippocampus post-Flx revealed robust transcriptomic reprogramming in the DG, with mature granule cells adopting a juvenile-like transcriptional profile, including upregulation of the developmental gene Sox11 . This was accompanied by increased BDNF signaling and enhanced structural remodeling in the mossy fiber pathway. Flx remodeled perisynaptic nets, a novel ECM structures in the DG, and targeted ECM degradation around granule cells reactivated SOX11. Flx treatment mitigated stress-induced fear generalization, and this was phenocopied by direct degradation of ECM in the DG. These findings identify ECM remodeling as a molecular substrate for Flx’s effects, linking induction of a developmental-like plasticity program and rejuvenation of mature granule cells to improvements in stress-induced overgeneralization.