Enhanced ryanodine-mediated calcium release in mutant PS1-expressing Alzheimer's mouse models.
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 3xTg-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.
Stutzmann
Grace E
GE
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA. grace.stutzmann@rosalindfranklin.edu
Smith
Ian
I
Caccamo
Antonella
A
Oddo
Salvatore
S
Parker
Ian
I
Laferla
Frank
F
D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics*; D007293:Inosine Triphosphate / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*
D015221:Potassium Channels; D053764:Presenilin-1; D019837:Ryanodine Receptor Calcium Release Channel; D007293:Inosine Triphosphate; D012433:Ryanodine