Upregulated Ca<sup>2+</sup> 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<sup>2+</sup> influx through membrane-resident voltage-gated Ca<sup>2+</sup> channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively pr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/14/2167 |
| _version_ | 1797407046866305024 |
|---|---|
| author | Temitope Adeoye Syed I. Shah Angelo Demuro David A. Rabson Ghanim Ullah |
| author_facet | Temitope Adeoye Syed I. Shah Angelo Demuro David A. Rabson Ghanim Ullah |
| author_sort | Temitope Adeoye |
| collection | DOAJ |
| description | Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca<sup>2+</sup> influx through membrane-resident voltage-gated Ca<sup>2+</sup> 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<sup>2+</sup> levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca<sup>2+</sup> release from the ER and downregulation of Ca<sup>2+</sup> buffering proteins. However, the precise consequence of impaired Ca<sup>2+</sup> signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca<sup>2+</sup> signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca<sup>2+</sup> signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> homeostasis mediated by intracellular stores in FAD. |
| first_indexed | 2024-03-09T03:35:35Z |
| format | Article |
| id | doaj.art-7be7f90cb2514c3c933243ce37cdee56 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T03:35:35Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-7be7f90cb2514c3c933243ce37cdee562023-12-03T14:49:39ZengMDPI AGCells2073-44092022-07-011114216710.3390/cells11142167Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s DiseaseTemitope Adeoye0Syed I. Shah1Angelo Demuro2David A. Rabson3Ghanim Ullah4Department of Physics, University of South Florida, Tampa, FL 33620, USADepartment of Physics, University of South Florida, Tampa, FL 33620, USADepartment of Neurobiology and Behavior, University of California, Irvine, CA 92697, USADepartment of Physics, University of South Florida, Tampa, FL 33620, USADepartment of Physics, University of South Florida, Tampa, FL 33620, USANeurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca<sup>2+</sup> influx through membrane-resident voltage-gated Ca<sup>2+</sup> 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<sup>2+</sup> levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca<sup>2+</sup> release from the ER and downregulation of Ca<sup>2+</sup> buffering proteins. However, the precise consequence of impaired Ca<sup>2+</sup> signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca<sup>2+</sup> signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca<sup>2+</sup> signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> homeostasis mediated by intracellular stores in FAD.https://www.mdpi.com/2073-4409/11/14/2167neuronal calcium signalingendoplasmic reticulumAlzheimer’sIP<sub>3</sub>Rneurotransmitter releasesynaptic transmission |
| spellingShingle | Temitope Adeoye Syed I. Shah Angelo Demuro David A. Rabson Ghanim Ullah Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease Cells neuronal calcium signaling endoplasmic reticulum Alzheimer’s IP<sub>3</sub>R neurotransmitter release synaptic transmission |
| title | Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease |
| title_full | Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease |
| title_fullStr | Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease |
| title_full_unstemmed | Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease |
| title_short | Upregulated Ca<sup>2+</sup> Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease |
| title_sort | upregulated ca sup 2 sup release from the endoplasmic reticulum leads to impaired presynaptic function in familial alzheimer s disease |
| topic | neuronal calcium signaling endoplasmic reticulum Alzheimer’s IP<sub>3</sub>R neurotransmitter release synaptic transmission |
| url | https://www.mdpi.com/2073-4409/11/14/2167 |
| work_keys_str_mv | AT temitopeadeoye upregulatedcasup2supreleasefromtheendoplasmicreticulumleadstoimpairedpresynapticfunctioninfamilialalzheimersdisease AT syedishah upregulatedcasup2supreleasefromtheendoplasmicreticulumleadstoimpairedpresynapticfunctioninfamilialalzheimersdisease AT angelodemuro upregulatedcasup2supreleasefromtheendoplasmicreticulumleadstoimpairedpresynapticfunctioninfamilialalzheimersdisease AT davidarabson upregulatedcasup2supreleasefromtheendoplasmicreticulumleadstoimpairedpresynapticfunctioninfamilialalzheimersdisease AT ghanimullah upregulatedcasup2supreleasefromtheendoplasmicreticulumleadstoimpairedpresynapticfunctioninfamilialalzheimersdisease |