Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice.
Presenilin mutations result in exaggerated endoplasmic reticulum (ER) calcium release in cellular and animal models of Alzheimer's disease (AD). In this study, we examined whether dysregulated ER calcium release in young 3xTg-AD neurons alters synaptic transmission and plasticity mechanisms before the onset of histopathology and cognitive deficits. Using electrophysiological recordings and two-photon calcium imaging in young (6-8 weeks old) 3xTg-AD and non-transgenic (NonTg) hippocampal slices, we show a marked increase in ryanodine receptor (RyR)-evoked calcium release within synapse-dense regions of CA1 pyramidal neurons. In addition, we uncovered a deviant contribution of presynaptic and postsynaptic ryanodine receptor-sensitive calcium stores to synaptic transmission and plasticity in 3xTg-AD mice that is not present in NonTg mice. As a possible underlying mechanism, the RyR2 isoform was found to be selectively increased more than fivefold in the hippocampus of 3xTg-AD mice relative to the NonTg controls. These novel findings demonstrate that 3xTg-AD CA1 neurons at presymptomatic ages operate under an aberrant, yet seemingly functional, calcium signaling and synaptic transmission system long before AD histopathology onset. These early signaling alterations may underlie the later synaptic breakdown and cognitive deficits characteristic of later stage AD.
Chakroborty
Shreaya
S
Department of Neuroscience, Rosalind Franklin University, The Chicago Medical School, North Chicago, Illinois 60064, USA.
Goussakov
Ivan
I
Miller
Megan B
MB
Stutzmann
Grace E
GE
D000544:Alzheimer Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D017966:Pyramidal Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D020033:Protein Isoforms; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium