@article {Stutzmann5180, author = {Grace E. Stutzmann and Ian Smith and Antonella Caccamo and Salvatore Oddo and Frank M. LaFerla and Ian Parker}, title = {Enhanced Ryanodine Receptor Recruitment Contributes to Ca2+ Disruptions in Young, Adult, and Aged Alzheimer{\textquoteright}s Disease Mice}, volume = {26}, number = {19}, pages = {5180--5189}, year = {2006}, doi = {10.1523/JNEUROSCI.0739-06.2006}, publisher = {Society for Neuroscience}, abstract = {Neuronal Ca2+ signaling through inositol triphosphate receptors (IP3R) and ryanodine receptors (RyRs) must be tightly regulated to maintain cell viability, both acutely and over a lifetime. Exaggerated intracellular Ca2+ levels have been associated with expression of Alzheimer{\textquoteright}s disease (AD) mutations in young mice, but little is known of Ca2+ dysregulations during normal and pathological aging processes. Here, we used electrophysiological recordings with two-photon imaging to study Ca2+ signaling in nontransgenic (NonTg) and several AD mouse models (PS1KI, 3xTg-AD, and APPSweTauP301L) at young (6 week), adult (6 months), and old (18 months) ages. At all ages, the PS1KI and 3xTg-AD mice displayed exaggerated endoplasmic reticulum (ER) Ca2+ signals relative to NonTg mice. The PS1 mutation was the predominant {\textquotedblleft}calciopathic{\textquotedblright} factor, because responses in 3xTg-AD mice were similar to PS1KI mice, and APPSweTauP301L mice were not different from controls. In addition, we uncovered powerful signaling interactions and differences between IP3R- and RyR-mediated Ca2+ components in NonTg and AD mice. In NonTg mice, RyR contributed modestly to IP3-evoked Ca2+, whereas the exaggerated signals in 3xTg-AD and PS1KI mice resulted primarily from enhanced RyR-Ca2+ release and were associated with increased RyR expression across all ages. Moreover, IP3-evoked membrane hyperpolarizations in AD mice were even greater than expected from exaggerated Ca2+ signals, suggesting increased coupling efficiency between cytosolic [Ca2+] and K+ channel regulation. We conclude that lifelong ER Ca2+ disruptions in AD are related to a modulation of RyR signaling associated with PS1 mutations and represent a discrete {\textquotedblleft}calciumopathy,{\textquotedblright} not merely an acceleration of normal aging.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/26/19/5180}, eprint = {https://www.jneurosci.org/content/26/19/5180.full.pdf}, journal = {Journal of Neuroscience} }