Upregulated Ca(2+) Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease

Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca(2+) influx through membrane-resident voltage-gated Ca(2+) channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca(2+) levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca(2+) release from the ER and downregulation of Ca(2+) buffering proteins. However, the precise consequence of impaired Ca(2+) signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca(2+) signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca(2+) signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca(2+) release from the ER increases the probability of neurotransmitter release in FAD. Moreover, over very short timescales (30–60 ms), the model exhibits activity-dependent and enhanced short-term plasticity in FAD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 ms), pathological Ca(2+) signaling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca(2+) homeostasis mediated by intracellular stores in FAD.