Enhanced ryanodine-mediated calcium release in mutant PS1-expressing Alzheimer's mouse models

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 sliceswe 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 Ca ²⁺ signals evoked by photoreleased IP₃ in cortical neurons from non-Tg mice. In contrast, the exaggerated signals in 3xTg-AD and PS1 _KI 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 Ca ²⁺ signaling in both neuronal physiology and pathophysiology, and point to presenilin-linked disruptions in RyR signaling as an important genetic factor in AD.