biostudies-literatureEstarellas CEuropean Social Fund PlusMinisterio de Ciencia e InnovaciónAgencia Estatal de Investigacion114878https://www.ebi.ac.uk/biostudies/studies/S-EPMC12925530biostudies-literatureUnknown29(3)In the dentate gyrus (DG), tight inhibitory control confines the activity of granule cells (GCs)-a key characteristic for its proposed role as a pattern separator. Nonetheless, a conundrum arises concerning the balance between sparseness of GC firing and the activity level needed for efficient transmission downstream to CA3. Using <i>in vivo</i> electrophysiology, pharmacogenetics, and computational modeling, we identified a synaptic plasticity mechanism that decouples excitation from inhibition, enhancing information encoding and transmission without compromising pattern separation. Long-term synaptic potentiation of the perforant pathway, in addition to strengthening the glutamatergic synapses into GCs, depressed feedforward perisomatic inhibition. Computational modeling revealed a functiScienceSynaptic plasticity in the perforant pathway drives inhibitory reorganization enhancing dentate gyrus functionality.PMC12925530MICIU/AEI/10.13039/501100011033PID2021-128158NB-C21PID2021-128158NB-C22PID2024-162400OB-C22PID2024-162400OB-C21FPI/1900/2016Perez-Cervera LCanals SLopez-Madrona VJPerez-Montoyo EMirasso CRCarames JMEstarellas CGarcia-Hernandez RAlvarez-Salvado EfalseSynaptic plasticity in the perforant pathway drives inhibitory reorganization enhancing dentate gyrus functionality.In the dentate gyrus (DG), tight inhibitory control confines the activity of granule cells (GCs)-a key characteristic for its proposed role as a pattern separator. Nonetheless, a conundrum arises concerning the balance between sparseness of GC firing and the activity level needed for efficient transmission downstream to CA3. Using <i>in vivo</i> electrophysiology, pharmacogenetics, and computational modeling, we identified a synaptic plasticity mechanism that decouples excitation from inhibition, enhancing information encoding and transmission without compromising pattern separation. Long-term synaptic potentiation of the perforant pathway, in addition to strengthening the glutamatergic synapses into GCs, depressed feedforward perisomatic inhibition. Computational modeling revealed a funct2026-01-01T00:00:00Z2026 Mar2026-07-16T18:47:46.719Z2026-07-12T03:07:52.067ZS-EPMC129255304173225310.1016/j.isci.2026.114878