Upregulated Ca²⁺ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease

Abstract

Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca²⁺ influx through membrane-resident voltage-gated Ca²⁺ channels (VGCCs). Also, 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. Alzheimer’s disease (AD) is marked by enhanced Ca²⁺ release from the ER and downregulation of Ca²⁺ buffering proteins. However, the precise consequence of impaired Ca²⁺ signalling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in-silico experiments of intracellular Ca²⁺ signalling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca²⁺ signalling on neurotransmitter release in AD. Our model predicts that enhanced Ca²⁺ release from the ER increases the probability of neurotransmitter release in AD. Moreover, over very short timescales (30-60 msec), the model exhibits activity-dependent and enhanced short-term plasticity in AD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 msec), pathological Ca²⁺ signalling 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 AD.