| Summary: | Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca<sup>2+</sup> influx through membrane-resident voltage-gated Ca<sup>2+</sup> 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<sup>2+</sup> levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca<sup>2+</sup> release from the ER and downregulation of Ca<sup>2+</sup> buffering proteins. However, the precise consequence of impaired Ca<sup>2+</sup> signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca<sup>2+</sup> signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca<sup>2+</sup> signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> homeostasis mediated by intracellular stores in FAD.
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