Upregulated Ca 2+ 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 Ca influx through membrane-resident voltage-gated Ca channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a m...

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Bibliographic Details
Published inCells (Basel, Switzerland) Vol. 11; no. 14
Main Authors Adeoye, Temitope, Shah, Syed I, Demuro, Angelo, Rabson, David A, Ullah, Ghanim
Format Journal Article
LanguageEnglish
Published Switzerland 11.07.2022
Subjects
Alzheimer Disease - metabolism
Animals
Calcium - metabolism
Endoplasmic Reticulum - metabolism
Neurotransmitter Agents - metabolism
IP3R
neuronal calcium signaling
synaptic transmission
depression
facilitation
neurotransmitter release
Alzheimer’s
endoplasmic reticulum
short-term plasticity
synchronous release
asynchronous release
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Summary:Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca influx through membrane-resident voltage-gated Ca 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 levels. Familial Alzheimer's disease (FAD) is marked by enhanced Ca release from the ER and downregulation of Ca buffering proteins. However, the precise consequence of impaired Ca signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca 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 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 homeostasis mediated by intracellular stores in FAD.
ISSN:2073-4409