Abstract: Intracellular Ca2+ signaling involves Ca2+ liberation through both inositol triphosphate and ryanodine receptors (IP3R and RyR). However, little is known of the functional interactions between these Ca2+ sources in either neuronal physiology, or during Ca2+ disruptions associated with Alzheimer's disease (AD). By the use of whole-cell recordings and 2-photon Ca2+ imaging in cortical slices we distinguished between IP3R- and RyR-mediated Ca2+ components in nontransgenic (non-Tg) and AD mouse models and demonstrate powerful signaling interactions between these channels. Ca2+-induced Ca2+ release (CICR) through RyR contributed modestly to Ca2+ signals evoked by photoreleased IP3 in cortical neurons from non-Tg mice. In contrast, the exaggerated signals in 3×Tg-AD and PS1KI mice resulted primarily from enhanced CICR through RyR, rather than through IP3R, and were associated with increased RyR expression levels. Moreover, membrane hyperpolarizations evoked by IP3 in neurons from AD mouse models were even greater than expected simply from the exaggerated Ca2+ signals, pointing to an increased coupling efficiency between cytosolic [Ca2+] and K+ channel regulation. Our results highlight the critical roles of RyR-mediated Ca2+ signaling in both neuronal physiology and pathophysiology, and point to presenilin-linked disruptions in RyR signaling as an important genetic factor in AD.