GABAergic inhibition differentially gates recruitment of dentate gyrus interneurons by lateral entorhinal cortex inputs

By keeping its activity low even when strongly stimulated, the dentate gyrus (DG) serves as the main entry point to the hippocampal circuit and helps separate different patterns of incoming information. However, the mechanisms supporting this low-level activity remain unclear. Here, we used in vitro patch-clamp recordings, two-photon calcium imaging, and optogenetics in hippocampal slices from adult mice to understand how local GABAergic interneurons control lateral entorhinal cortex (LEC) input-mediated drive in the DG. Under control conditions, LEC inputs rarely elicited granule cell (GC) firing because GABA A receptor-mediated inhibition strongly restrained GC excitability. Whole-cell patch clamp recordings of DG interneurons revealed that LEC activation prevalently recruited fast-spiking parvalbumin-expressing and molecular layer interneurons, while most dendrite-targeting interneuron types responded only weakly to LEC input and fired action potentials only after feedback excitation from GCs was enhanced by pharmacological block of GABA A -receptors. Optogenetic inhibition of defined interneuron populations showed that silencing dendrite-targeting interneurons caused a larger increase in GC population spiking than silencing perisomatic-targeting interneurons, suggesting that both molecular layer and feedback-recruited interneurons have a prevalent role in controlling DG recruitment after an increase in LEC drive. In summary, our data indicate that GABAergic inhibition engages distinct DG interneuron types in feedforward and feedback circuits to tightly gate entorhinal inputs. By maintaining sparse GC firing, this dynamic inhibitory gating supports the role of the dentate gyrus in the hippocampal pattern-separation process.