Upregulated Ca2+ 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 Ca2+ influx through membrane-resident voltage-gated Ca2+ 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 Ca2+ levels. Familial Alzheimer's disease (FAD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca2+ signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in FAD. Moreover, over very short timescales (30 similar to-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 (similar to 450 ms), pathological Ca2+ 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 Ca2+ homeostasis mediated by intracellular stores in FAD.

Automated summary

The release of neurotransmitters is regulated by Ca2+ influx through voltage-gated Ca2+ channels at presynaptic terminals. The endoplasmic reticulum (ER) in neuronal axonal terminals plays a modulatory role in synaptic transmission by regulating Ca2+ levels. In familial Alzheimer's disease (FAD), enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins occur. This study investigates the impact of aberrant Ca2+ signaling on neurotransmitter release in FAD using computational modeling. The findings suggest that enhanced Ca2+ release increases the probability of neurotransmitter release in FAD, and it leads to activity-dependent short-term plasticity. However, during prolonged stimulation, pathological Ca2+ signaling causes depression and desynchronization, resulting in unreliable synaptic operation.