Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates

The endoplasmic reticulum (ER)'s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in hiPSC-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca 2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca 2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca 2+ bursts. The ER morpho-regulatory control of Ca 2+ refill speed thus constitutes a switch on neuronal activity. These results expose the selective vulnerability of Ca 2+ -firing cells to ER structural disruptions, rationalising ER dysfunction in neurodegeneration. This mechanism could apply universally to Ca 2+ -firing cells.