CHEMOGENETIC MANIPULATION OF MEDIAL ENTORHINAL CORTEX INPUTS TO THE DENTATE GYRUS REVEALS SPECIFIC ROLES OF DISTINCT HIPPOCAMPAL INTERNEURON TYPES IN THE INTEGRATION OF SPATIAL MEMORY

The dentate gyrus (DG) in the hippocampus plays a key role in the emergence and storage of spatial and contextual representations. Stellate cells in layer II of the medial entorhinal cortex (MEC) are providing the major spatial input to the DG. Previous experiments demonstrated significant effects of MEC layer II chemogenetic manipulation on granule cell (GC) spatial representation (Kilias et al., in preparation). Remarkably, MEC layer II depolarization resulted in a major shutdown of spatially-modulated GCs (place cells). In light of this observation, we hypothesized that feedforward and feedback inhibition via local GABAergic interneurons tightly regulate the integration and processing of spatial information reaching the DG. To address this hypothesis, we employed chemogenetic tools (hM3Dq/hM4Di) to modulate MEC layer II inputs and 2-photon calcium recording of DG interneurons in head-fixed mice navigating through familiar virtual environments. Our preliminary results show that enhanced MEC layer II recruitment via hM3Dq activation causes a significant upregulation of hippocampal interneuron activity, suggesting their direct involvement in the silencing of GCs. In order to specify the molecular identity of the imaged interneurons, we developed a combined approach based on (1) in vivo 2-photon volumetric imaging comprising the recorded interneurons; (2) post-hoc immunohistochemical identification of interneuron types, and (3) 3D reconstruction by co-registering in vivo volumetric data and post-hoc confocal images. By revealing the molecular identity of each imaged interneuron, this method allows to dissect the specific role of distinct GABAergic subpopulations within the entorhinal-hippocampal circuitry in establishing and maintaining spatial memories.