NDNF-EXPRESSING INTERNEURONS PROVIDE FEEDBACK AND FEEDFORWARD DENDRITIC INHIBITION TO DENTATE GYRUS GRANULE CELLS TO CONTROL THE FLEXIBLE ENCODING OF ENVIRONMENTAL CHANGES

Hippocampal principal cell populations rapidly change their activity patterns in response to sudden contextual changes, while preserving previously acquired memory traces. Although a wealth of studies has investigated the circuit mechanisms underlying the differentiation of familiar from novel experiences, the role of dendritic inhibition in context discrimination is less understood. By applying electrophysiology, electron microscopy, 2-Photon in vivo imaging and chemogenetics, we examined the role of neuron-derived neurotrophic factor-expressing GABAergic interneurons (NDNFIs) in the dentate gyrus (DG), and their contribution to encoding contextual information. We found that two subtypes of DG NDNFIs provide slow inhibition to distal dendritic shafts of principal cells: those with somata within the molecular layer are rapidly recruited by entorhinal cortex inputs, and those located in the hilus are predominantly activated by feedback excitation provided by local principal cells. In head-fixed mice exploring virtual realities, DG NDNFIs change their activity dynamics in new as compared to familiarized contexts and upon unexpected changes in a familiar environment, e.g. after introducing a novel goal. Chemogenetic recruitment of NDNFIs caused generalization of principal cell assemblies among similar contexts but left their remapping between highly dissimilar contexts unperturbed, indicating their role in controlling the flexible encoding of similar memory representations. Taken together, we propose that DG NDNFIs play a key role in gating input plasticity at principal cell dendrites, thereby protecting acquired memory traces during sudden changes in otherwise familiar environments.