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

• Published in: bioRxiv
• Main Authors: Adeoye, Temitope, Shah, Syed I, Demuro, Angelo, Rabson, David A, Ullah, Ghanim
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.04.2022
• Subjects: Alzheimer's disease; Animal models; Calcium (intracellular); Calcium (reticular); Calcium buffering; Calcium channels; Calcium channels (voltage-gated); Calcium homeostasis; Calcium influx; Calcium signalling; Endoplasmic reticulum; Exocytosis; Hippocampus; Homeostasis; Hyperactivity; Intracellular; Intracellular signalling; Neurodegenerative diseases; Neurotransmitter release; Synaptic depression; Synaptic transmission; Synchronization
• DOI: 10.1101/2022.04.21.489060

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. Competing Interest Statement The authors have declared no competing interest.