Aberrant medial entorhinal cortex dynamics link tau pathology to spatial memory impairment

ABSTRACT Tau pathology in the entorhinal cortex (EC) is associated with spatial memory decline in aging and early-stage Alzheimer’s disease, but its impact on EC computations during learning is not well understood. We performed longitudinal two-photon calcium imaging of layer 2 excitatory neurons in the medial EC (MEC) of PS19 tauopathy mice over 10 days of an operant spatial learning task. Male PS19 mice showed marked learning impairments accompanied by dysregulated MEC activity and unstable spatial coding. Their activity also showed weakened representations in cue-poor relative to cue-rich regions, correlated with attenuated speed modulation. These changes suggest that impaired path integration destabilizes MEC spatial maps, leading to impaired spatial memory. In contrast, female PS19 mice exhibited only mild behavioral and neural deficits despite a comparable tau burden, suggesting sex-specific resilience. Among MEC cell types, pyramidal cells accumulated more phosphorylated tau than stellate cells and displayed the most severe functional disruption, linking cellular tau load to circuit dysfunction. Finally, general linear models of MEC activity reliably predicted learning performance, highlighted particularly strong contributions from non-grid and pyramidal cells, and accurately classified PS19 versus wild-type mice. These findings identify aberrant MEC dynamics as a key circuit mechanism underlying tau-related spatial memory deficits and point to early diagnostic and circuit-targeted therapeutic strategies.