Early Presynaptic and Postsynaptic Calcium Signaling Abnormalities Mask Underlying Synaptic Depression in Presymptomatic Alzheimer's Disease Mice

Department of Neuroscience, Rosalind Franklin University/The Chicago Medical School, North Chicago, Illinois 60064, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2012; 32(24):8341-53. DOI: 10.1523/JNEUROSCI.0936-12.2012
Source: PubMed


Alzheimer's disease (AD)-linked presenilin (PS) mutations result in pronounced endoplasmic reticulum calcium disruptions that occur before detectable histopathology and cognitive deficits. More subtly, these early AD-linked calcium alterations also reset neurophysiological homeostasis, such that calcium-dependent presynaptic and postsynaptic signaling appear functionally normal yet are actually operating under aberrant calcium signaling systems. In these 3xTg-AD mouse brains, upregulated ryanodine receptor (RyR) activity is associated with a shift toward synaptic depression, likely through a reduction in presynaptic vesicle stores and increased postsynaptic outward currents through small-conductance calcium-activated potassium SK2 channels. The deviant RyR-calcium involvement in the 3xTg-AD mice also compensates for an intrinsic predisposition for hippocampal long-term depression (LTD) and reduced long-term potentiation (LTP). In this study, we detail the impact of disrupted RyR-mediated calcium stores on synaptic transmission properties, LTD, and calcium-activated membrane channels of hippocampal CA1 pyramidal neurons in presymptomatic 3xTg-AD mice. Using electrophysiological recordings in young 3xTg-AD and nontransgenic (NonTg) hippocampal slices, we show that increased RyR-evoked calcium release in 3xTg-AD mice "normalizes" an altered synaptic transmission system operating under a shifted homeostatic state that is not present in NonTg mice. In the process, we uncover compensatory signaling mechanisms recruited early in the disease process that counterbalance the disrupted RyR-calcium dynamics, namely increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. Because AD is increasingly recognized as a "synaptic disease," calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD.

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Available from: Shreaya Chakroborty,
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    • "It would be worthwhile to investigate whether intranasal insulin treatment of models of tauopathies for a longer time reduces tau hyperphosphorylation. Interestingly, the activity-dependent CaMKII phosphorylation at Thr286 was dramatically increased in the 3xTg-AD mouse brains, suggesting a marked increase in the kinase activity. This increase might result from the increased intracellular calcium influx seen in the 3xTg-AD brain (Chakroborty et al., 2012). "
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    • "However when RyRs are blocked and enhanced CICR effect was suppressed, the AD neurons demonstrated enhanced basal synaptic transmission and altered short and long term plasticity. This may suggest that RyR-mediated Ca2+ signals have a prominent inhibitory effect in basal synaptic transmission and presynaptic neurotransmitter release in the AD mice [135,168]. These data were further confirmed by showing that sub-chronic stabilization of ER Ca2+ signaling earlier in the disease process has beneficial effects on synaptic transmission and plasticity abnormalities in presymptomatic 3xTg-AD mice and adult PS1M146V/APPswe double transgenic mouse model, while having little effect in non-transgenic controls [135,168]. "
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    ABSTRACT: Perturbed Endoplasmic Reticulum (ER) calcium (Ca2+) homeostasis emerges as a central player in Alzheimer disease (AD). Accordingly, different studies have reported alterations of the expression and the function of Ryanodine Receptors (RyR) in human AD-affected brains, in cells expressing familial AD-linked mutations on the beta amyloid precursor protein (betaAPP) and presenilins (the catalytic core in gamma-secretase complexes cleaving the betaAPP, thereby generating amyloid beta (Abeta) peptides), as well as in the brain of various transgenic AD mice models. Data converge to suggest that RyR expression and function alteration are associated to AD pathogenesis through the control of: i) betaAPP processing and Abeta peptide production, ii) neuronal death; iii) synaptic function; and iv) memory and learning abilities. In this review, we document the network of evidences suggesting that RyR could play a complex dual "compensatory/protective versus pathogenic" role contributing to the setting of histopathological lesions and synaptic deficits that are associated with the disease stages. We also discuss the possible mechanisms underlying RyR expression and function alterations in AD. Finally, we review recent publications showing that drug-targeting blockade of RyR and genetic manipulation of RyR reduces Abeta production, stabilizes synaptic transmission, and prevents learning and memory deficits in various AD mouse models. Chemically-designed RyR "modulators" could therefore be envisioned as new therapeutic compounds able to delay or block the progression of AD.
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    • "Exaggerated Ca 2+ signals in response to IP 3 -or RyR activation have been consistently described in various types of cells harboring AD-related PS mutations (Cheung et al. 2008; Ito et al. 1994; Muller et al. 2011; Schneider et al. 2001; Smith et al. 2005; Stutzmann et al. 2004, 2006, 2007). Exaggerated Ca 2+ release from the intracellular Ca 2+ stores has been suggested to act as a compensatory mechanism balancing pathologically diminished synaptic transmission (Chakroborty et al. 2012b). On the other hand, as mentioned above, stimulation of RyRs with caffeine in APP-overexpressing HEK293 cells leads to a higher release of Aβ into the extracellular space (Querfurth et al. 1997). "
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