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Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective

Valentina Davi1, Pierre Parutto1, Yuyi Zhang2

  • 1Department of Clinical Neurosciences, UK Dementia Research Institute at University of Cambridge, Cambridge, UK.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 31, 2026
PubMed
Summary
This summary is machine-generated.

Endoplasmic reticulum (ER) structure controls calcium (Ca2+) replenishment speed in neurons. ER shape disruptions impair neuronal activity and Ca2+ firing, explaining neurodegenerative disease links.

Keywords:
calcium oscillationsendoplasmic reticulum Ca2+ refillendoplasmic reticulum morphologyhuman iPSC‐derived neuronsmodellingneurodegenerative diseasesneuronal firing

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Area of Science:

  • Cell Biology
  • Neuroscience
  • Biophysics

Background:

  • Endoplasmic reticulum (ER) morphology is crucial for cellular function, with defects linked to neurodegenerative disorders.
  • The specific reasons why neuronal ER structure perturbations cause disease remain unclear.

Purpose of the Study:

  • To investigate the structure-function relationship of the ER in neurons.
  • To understand how ER architecture influences calcium (Ca2+) dynamics and neuronal activity.

Main Methods:

  • Utilized human inducible pluripotent stem cell (hiPSC)-derived cortical neurons.
  • Combined live imaging of neuronal firing bursts with ER ultrastructural manipulation.
  • Employed physical simulations to model ER structure-function principles.

Main Results:

  • Established that neuronal ER architecture dictates Ca2+ replenishment speed.
  • Demonstrated that altered ER structure impairs network ER luminal connectivity and Ca2+ propagation.
  • Showed that perturbed ER shape abolishes Ca2+ firing and contraction in skeletal muscle cells.

Conclusions:

  • Neuronal ER morphology regulates Ca2+ refill speed, acting as a switch for neuronal activity.
  • Ca2+-firing cells exhibit selective vulnerability to ER structural disruptions.
  • ER structural integrity is vital for neuronal function and may be universally important for Ca2+-firing cells.