Antidepressants reactivate developmental plasticity through remodeling of extracellular matrix

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders, yet their molecular mechanisms of action remain poorly understood. Here, we show that chronic treatment with the SSRI fluoxetine reinstates a developmental plasticity program in the dentate gyrus (DG) by remodeling the extracellular matrix (ECM). Fluoxetine elicited a robust transcriptomic response in the DG, where mature granule cells adopted a juvenile-like profile. This shift was characterized by upregulation of the transcription factor SOX11 and the neurotrophic factor BDNF, as well as decreased ECM and enhanced structural remodeling of granule cell axon terminals. Direct enzymatic degradation of ECM in the DG reactivated SOX11 in mature granule cells. At the behavioral level, fluoxetine mitigated stress-induced fear generalization, an endophenotype of mood and anxiety disorders. This effect was phenocopied by ECM degradation, suggesting that ECM remodeling and granule cell rejuvenation are key mechanisms underlying the effects of fluoxetine, and possibly other antidepressants, on fear generalization.