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

ABSTRACT 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 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. Further, perturbed ER shape also abolishes Ca ²⁺ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca ²⁺ ‐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 Ca ²⁺ ‐firing cells.