The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Functional network activity alterations are one of the earliest hallmarks of Alzheimer’s disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans. ### Competing Interest Statement The authors have declared no competing interest. * AAV : adeno-associated virus ACB : nucleus accumbens AD : Alzheimer’s disease BLA : baso-lateral amygdala BOLD : blood-oxygen-level-dependent DG : dentate gyrus DMN : default-mode network ENTl : lateral entorhinal cortex ILA : infralimbic area mPFC : medial prefrontal cortex ofMRI : optogenetics functional MRI ReHo : regional homogeneity rsfMRI : resting state functional MRI