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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.

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