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

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 human inducible Pluripotent Stem Cells (hiPSC)-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca²⁺ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca²⁺ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca²⁺ bursts. The ER morpho-regulatory control of Ca²⁺ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca²⁺ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca²⁺-firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca²⁺-firing cells.