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: 6.75). 06/2012; 32(24):8341-53. DOI: 10.1523/JNEUROSCI.0936-12.2012
Source: PubMed

ABSTRACT 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, Aug 09, 2015
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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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    Experimental Neurology 06/2014; 261. DOI:10.1016/j.expneurol.2014.06.004 · 4.62 Impact Factor
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    • "Other postsynaptic mechanisms were also discussed by Ittner et al. (2010). A number of studies have also shown that prior to neuronal loss, htau induces synaptic dysfunctions by presynaptic mechanisms which reduce the probability of neurotransmitter release (Yoshiyama et al., 2007; Polydoro et al., 2009; Chakroborty et al., 2012; Tai et al., 2012). The presynaptic mechanisms were "
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    Frontiers in Cellular Neuroscience 02/2014; 8:34. DOI:10.3389/fncel.2014.00034 · 4.18 Impact Factor
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    • "Likewise, an increase in presynaptic vesicle release has been demonstrated in a ryanodine receptor-calcium dependent manner in AD mouse models (Chakroborty et al., 2009, 2012b; Nizami et al., 2010; Shimizu et al., 2008). The likely resulting reduction in vesicle stores may be associated with the increased synaptic depression observed in AD mouse models (Chakroborty et al., 2012b; Palop and Mucke, 2010). Presenilin also associates with and regulates inositol triphosphate receptor activity. "
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