The origins of this approach are based on the knowledge that, in AD model systems, it is predominantly RyR-mediated responses that underlie aberrant intracellular Ca2+ signaling within synaptic compartments and contribute to altered synaptic homeostasis, and the observation that acute dantrolene in vitro can normalize ER Ca2+ signaling aberrations in presymptomatic AD mice [12]. This evidence concerns the gene RYR2 and Alzheimer disease.