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Disruptions in intracellular Ca²⁺ signaling are proposed to underlie the pathophysiology of Alzheimer's disease (AD), and it has recently been shown that AD-linked mutations in the presenilin 1 gene (PS1) enhance inositol triphosphate (IP₃)-mediated Ca²⁺ liberation in nonexcitable cells. However, little is known of these actions in neurons, which are the principal locus of AD pathology. We therefore sought to determine how PS1 mutations affect Ca²⁺ signals and their subsequent downstream effector functions in cortical neurons. Using whole-cell patch-clamp recording, flash photolysis, and two-photon imaging in brain slices from 4-5-week-old mice, we show that IP₃-evoked Ca²⁺ responses are more than threefold greater in PS1_M146V knock-in mice relative to age-matched nontransgenic controls. Electrical excitability is thereby reduced via enhanced Ca²⁺ activation of K⁺ conductances. Action potential …