In Vivo Analysis of Medial Perforant Path-Evoked Excitation and Inhibition in Dentate Granule Cells

Across brain regions and species, the dynamics and balance of excitation and inhibition critically determine neuronal firing. The hippocampal dentate gyrus is a brain area thought to be strongly regulated by inhibition. In vivo, it exhibits remarkably sparse activity, a characteristic proposed to underlie computational tasks like pattern separation. Several populations of interneurons mediate strong feedforward as well as feedback inhibition onto granule cells. However, how the dynamics of inhibition controls granule cell activity in vivo is insufficiently studied. Using two-photon in vivo Ca²⁺ imaging in mice of either sex, we show that sensory stimulation activates only a small number of dentate gyrus granule cells, while inducing widespread inhibition across the remaining granule cell population. Dual-color imaging of both bulk medial perforant path activity and individual granule cell activity allowed us to probe input-output conversion in this pathway. To examine the interplay of MPP-evoked excitation and inhibition at the cellular level, we used in vivo whole-cell patch-clamp recordings, while simultaneously photo-activating MPP inputs. Our findings reveal that MPP-triggered inhibition is fast, significantly larger than excitation, and long-lasting. These results reveal specific properties of inhibition in the dentate gyrus inhibition that are likely crucial for its computational functions, in maintaining sparse activity with a high signal-to-noise ratio.