Login / Signup

Upregulated Ca 2+ Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer's Disease.

Temitope AdeoyeSyed I ShahAngelo DemuroDavid A RabsonGhanim Ullah
Published in: Cells (2022)
Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca 2+ influx through membrane-resident voltage-gated Ca 2+ 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 2+ levels. Familial Alzheimer's disease (FAD) is marked by enhanced Ca 2+ release from the ER and downregulation of Ca 2+ buffering proteins. However, the precise consequence of impaired Ca 2+ signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca 2+ signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca 2+ signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca 2+ 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 2+ 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 2+ homeostasis mediated by intracellular stores in FAD.
Keyphrases
  • endoplasmic reticulum
  • protein kinase
  • multiple sclerosis
  • mass spectrometry
  • brain injury
  • early onset
  • multidrug resistant
  • quality improvement
  • cerebral ischemia
  • optical coherence tomography
  • peripheral nerve