Synaptic 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 functional reorganization of the DG inhibitory network that decorrelated excitation/inhibition, enhanced GC burst firing, and improved temporal and spatial discrimination within the entorhinal-cortex-DG-CA3 network. Consistently, targeting parvalbumin + interneurons to reduce perisomatic inhibition during memory encoding improved pattern separation in freely behaving mice. Overall, our findings uncover a plasticity mechanism that boosts DG output while preserving its pattern separation function.