Enhanced Ryanodine‐Mediated Calcium Release in Mutant PS1‐Expressing Alzheimer's Mouse Models

Abstract: Intracellular Ca 2+ signaling involves Ca 2+ liberation through both inositol triphosphate and ryanodine receptors (IP 3 R and RyR). However, little is known of the functional interactions between these Ca 2+ sources in either neuronal physiology, or during Ca 2+ disruptions associated with Alzheimer's disease (AD). By the use of whole‐cell recordings and 2‐photon Ca 2+ imaging in cortical slices we distinguished between IP 3 R‐ and RyR‐mediated Ca 2+ components in nontransgenic (non‐Tg) and AD mouse models and demonstrate powerful signaling interactions between these channels. Ca 2+ ‐induced Ca 2+ release (CICR) through RyR contributed modestly to Ca 2+ signals evoked by photoreleased IP 3 in cortical neurons from non‐Tg mice. In contrast, the exaggerated signals in 3×Tg‐AD and PS1 KI mice resulted primarily from enhanced CICR through RyR, rather than through IP 3 R, and were associated with increased RyR expression levels. Moreover, membrane hyperpolarizations evoked by IP 3 in neurons from AD mouse models were even greater than expected simply from the exaggerated Ca 2+ signals, pointing to an increased coupling efficiency between cytosolic [Ca 2+ ] 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.