CIRCUIT-LEVEL ALTERATIONS IN THE ENTORHINAL–HIPPOCAMPAL NETWORK IN TAUOPATHY

Early dysfunction of the entorhinal–hippocampal circuit is a foundational hallmark of tauopathies, most notably Alzheimer’s disease, where it acts as a critical link between neuropathology and cognitive decline. Yet, how activity is altered across connected circuit elements remains poorly understood. Using complementary one- and two-photon calcium imaging, we examined neural activity across defined nodes of the entorhinal–hippocampal circuit in PS19 mice, a transgenic model of tauopathy, at an intermediate disease stage (~8 months), alongside age-matched controls. One-photon calcium imaging of individual neurons in the dentate gyrus (DG), one of the primary input areas of the entorhinal cortex (EC) layer II neurons, during freely moving spatial navigation revealed elevated neuronal activity in PS19 mice, independent of movement speed. To determine whether upstream cortical drive contributes to these changes, we next performed two-photon axonal calcium imaging of EC layer II projections to the DG during head-fixed navigation. This revealed an increase in the amplitude of activity in entorhinal inputs, suggesting altered cortical input to the hippocampus (HPC). To resolve how these changes manifest in distinct DG cell types, we are currently conducting two-photon imaging of granule and mossy cells. Preliminary analyses indicate elevated neural activity in mossy cells, accompanied by deficits in spatial information-processing, pointing to cell-type specific changes and circuit-level computational alterations within the DG microcircuit. Our multi-scale imaging approach reveals how altered entorhinal input and cell-type specific DG activity interact to shape EC-HPC circuit dysfunction in tauopathy, providing a framework for dissecting circuit-level mechanisms of disease progression.