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 feed-forward as well as feedback inhibition onto granule cells. However, how the dynamics of inhibition controls granule cell activity in-vivo is insufficiently studied. Using 2-photon in-vivo Ca-imaging in mice of either sex, we show that sensory stimulation activates only a small number of dentate gyrus granule cells, while inducing wide-spread 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-noise ratio. This study investigates the super- and sub-threshold computations of dentate gyrus granule cells to an incoming stimulus signal through the medial perforant path. This pathway is the main connection transferring information from the medial entorhinal cortex layer II into the hippocampus proper. The role of the granule cell network is thought to be crucial for the encoding of new environments and thereby the forming of new memories. Our data directly elucidate the in-vivo dynamics of excitation and inhibition in the dentate gyrus using both in-vivo imaging and electrophysiology. These findings add to the understanding of the overall sparse code of the dentate gyrus and can be crucial for future studies investigating how hippocampal codes are generated from entorhinal cortex inputs.

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PMID: 41326203