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Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub\u2010Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)\u2010derived cortical neurons, alongside physical simulations, we establish a key ER structure\u2010function principle: neuronal ER architecture dictates Ca\n                    <jats:sup>2+<\/jats:sup>\n                    replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca\n                    <jats:sup>2+<\/jats:sup>\n                    bursts. The ER morpho\u2010regulatory control of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca\n                    <jats:sup>2+<\/jats:sup>\n                    firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010firing 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\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010firing cells.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521101","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T19:28:26Z","timestamp":1774985306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability"],"prefix":"10.1002","volume":"13","author":[{"given":"Valentina","family":"Davi","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences UK Dementia Research Institute at University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Parutto","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences UK Dementia Research Institute at University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physics University of California  San Diego, La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasuku","family":"Konno","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences UK Dementia Research Institute at University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Crapart","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences UK Dementia Research Institute at University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Pereira","sequence":"additional","affiliation":[{"name":"GIMM \u2013 Gulbenkian Institute for Molecular Medicine Avenida Prof. Egas Moniz  Lisboa Portugal"},{"name":"Faculdade de Medicina Universidade De Lisboa Av. 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