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...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2022-07, Vol.11 (14), p.2167
Main Authors: Adeoye, Temitope, Shah, Syed I., Demuro, Angelo, Rabson, David A., Ullah, Ghanim
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimer’s
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
IP3R
Ligands
Neurodegenerative diseases
neuronal calcium signaling
Neurotransmitter release
Physiology
Sensors
Signal transduction
Synaptic depression
Synaptic transmission
Synchronization
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Summary: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 (30–60 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 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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11142167