Fig. 7

Proposed role of RyR-Ca²⁺ signaling in early impairment of short term plasticity at the CA3-CA1 synapse in Alzheimer’s disease. Normal: In presynaptic CA3 terminals, RyR-evoked Ca²⁺-Induced-Ca²⁺-Release (CICR) can trigger spontaneous neurotransmitter release. During high frequency activity (such as a train of action potentials), CICR is evoked by voltage-gated Ca²⁺ influx to increase residual Ca²⁺ levels and release probability. Postsynaptically, in CA1 terminals, NMDAR-mediated Ca²⁺ signals are amplified by RyR-CICR in dendritic spines, a phenomenon required for plasticity induction. In other plasticity pathways, the mGluA-PLC pathway generates IP₃, activating IP₃R. Activation of IP₃Rs produces regenerative Ca²⁺ waves that support plasticity and gene expression. RyR-Ca²⁺ also activates SK channels that modulate membrane excitability and frequency of action potential firing. Thus, optimum levels of Ca²⁺ signaling and synaptic plasticity proteins like synaptophysin and PSD in dendritic spines support maintenance of spine structure and signal transmission across the hippocampus, generating optimal levels of plasticity and normal memory function. Early AD: Presynaptically, increased RyR expression greatly increases CICR. Increased CICR alters vesicle cycling and cause depletion of vesicles from the readily releasable pool as well as the reserve pool. While this can be initially remedied by increasing neurotransmitter synthesis and vesicle cycling, such maladaptive mechanisms can potentially cause metabolic and oxidative stress leading to synapse loss. Postsynaptically, increased RyR-CICR can decrease PSD lengths and weaken synaptic integrity resulting in the loss of dendritic spines, specifically mushroom spines required for synaptic plasticity. Increased RyR-CICR can also increase SK channel activity which decreases neuronal excitability and increases threshold for induction of synaptic plasticity. Thus, greatly increased Ca²⁺ signaling and loss of proteins supporting synaptic plasticity result in the loss of synaptic integrity and dendritic mushroom spines and decreased signal transmission across the hippocampus. These results in early deficits in short and long term synaptic plasticity that ultimately causes memory impairments