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Neuronal Ca²⁺ signaling through inositol triphosphate receptors (IP₃R) and ryanodine receptors (RyRs) must be tightly regulated to maintain cell viability, both acutely and over a lifetime. Exaggerated intracellular Ca²⁺ levels have been associated with expression of Alzheimer's disease (AD) mutations in young mice, but little is known of Ca²⁺ dysregulations during normal and pathological aging processes. Here, we used electrophysiological recordings with two-photon imaging to study Ca²⁺ signaling in nontransgenic (NonTg) and several AD mouse models (PS1_KI, 3xTg-AD, and APP_SweTau_P301L) at young (6 week), adult (6 months), and old (18 months) ages. At all ages, the PS1_KI and 3xTg-AD mice displayed exaggerated endoplasmic reticulum (ER) Ca²⁺ signals relative to NonTg mice. The PS1 mutation was the predominant “calciopathic” factor, because responses in 3xTg-AD mice were similar to PS1_KI …