RYR2 and Alzheimer disease: Presynaptic RyR function is also increased in 3xTg AD mice and RyR activation by caffeine decreases the paired-pulse ratio of evoked CA1 field potentials to a greater extent in AD mice, as well as restoring normal frequency of spontaneously released vesicles, indicating increased facilitation of glutamate release by presynaptic RyRs [30].