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

doi:10.1196/annals.1379.025

Intracellular Ca²⁺ signaling involves Ca²⁺ liberation throughboth inositol triphosphate and ryanodine receptors (IP₃R andRyR). However, little is known of the functional interactionsbetween these Ca²⁺ sources in either neuronal physiology, orduring 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- andRyR-mediated Ca²⁺ components in nontransgenic (non-Tg) and ADmouse models and demonstrate powerful signaling interactionsbetween these channels. Ca²⁺-induced Ca²⁺ release (CICR) throughRyR contributed modestly to Ca²⁺ signals evoked by photoreleasedIP₃ in cortical neurons from non-Tg mice. In contrast, the exaggeratedsignals in 3xTg-AD and PS1_KI mice resulted primarily from enhancedCICR through RyR, rather than through IP₃R, and were associatedwith increased RyR expression levels. Moreover, membrane hyperpolarizationsevoked by IP₃ in neurons from AD mouse models were even greaterthan expected simply from the exaggerated Ca²⁺ signals, pointingto an increased coupling efficiency between cytosolic [Ca²⁺]and K⁺ channel regulation. Our results highlight the criticalroles of RyR-mediated Ca²⁺ signaling in both neuronal physiologyand pathophysiology, and point to presenilin-linked disruptionsin RyR signaling as an important genetic factor in AD.

Part III. Diagnostic Applications of Imaging to Alzheimer's Disease