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.

Download full-text


Available from: Shreaya Chakroborty, Oct 06, 2015
32 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Decreased brain insulin signaling has been found recently in Alzheimer disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, the underlying mechanisms are unknown. Here, we treated 9-month-old 3xTg-AD mice, a commonly used mouse model of AD, with daily intranasal administration of insulin for seven days and then studied brain abnormalities of the mice biochemically and immunohistochemically. We found that intranasal insulin restored insulin signaling, increased the levels of synaptic proteins, and reduced Aβ40 level and microglia activation in the brains of 3xTg-AD mice. However, this treatment did not affect the levels of glucose transporters and O-GlcNAcylation or tau phosphorylation. Our findings provide a mechanistic insight into the beneficial effects of intranasal insulin treatment and support continuous clinical trials of intranasal insulin for the treatment of AD.
    Experimental Neurology 06/2014; 261. DOI:10.1016/j.expneurol.2014.06.004 · 4.70 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Molecular Neurodegeneration 06/2014; 9(1):21. DOI:10.1186/1750-1326-9-21 · 6.56 Impact Factor
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Behavioral and electrophysiological studies of Alzheimer's disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-β plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms.
    Frontiers in Cellular Neuroscience 02/2014; 8:34. DOI:10.3389/fncel.2014.00034 · 4.29 Impact Factor
Show more