We propose that the intrinsic vulnerability of entorhinal cortex layer II reelin‑positive stellate grid cells stems from their high‑frequency firing‑induced mitochondrial calcium overload, which activates the phosphatase calcineurin and drives early tau phosphorylation before neurofibrillary tangle formation. This hypothesis extends the existing observations that these neurons lack calbindin, experience ER stress, and show presynaptic deficits [1][2][3][4]. Specifically, sustained depolarization during spatial navigation elevates intracellular Ca2+ that exceeds mitochondrial buffering capacity, leading to opening of the permeability transition pore, ROS production, and activation of calcineurin. Calcineurin dephosphorylates inhibitor‑1, thereby increasing PP1 activity toward tau, promoting phosphorylation at AT8‑sensitive sites. Importantly, this cascade predicts that pharmacological inhibition of mitochondrial calcium uptake (e.g., with Ru360) or calcineurin blockade (e.g., with FK506) in young rTgTauEC mice will prevent soluble tau‑induced LTP impairment and synaptic vesicle clustering deficits without altering tau expression levels. Conversely, genetic enhancement of mitochondrial calcium efflux (overexpressing NCLX) should rescue grid cell firing stability and delay the spread of tau to hippocampal CA1 via the perforant pathway. Falsifiable outcomes: (1) If Ru360 or FK506 fails to ameliorate presynaptic deficits or slows tau spread in EC‑hippocampal circuits, the calcium‑calceinuerin axis is not a primary driver; (2) If NCLX overexpression does not improve grid cell phase precession or reduces tau propagation, mitochondrial mishandling of calcium is insufficient to explain selective vulnerability. These outcomes can be tested using in vivo calcium imaging (GCaMP6f) combined with electrophysiology and PET‑compatible tau tracers in the rTgTauEC model, providing a mechanistic link between spatial network activity, organelle stress, and the initiation of tauopathy.