Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates

Davi, V.; Parutto, P.; Crapart, C.; Zhang, Y.; Konno, T.; Chambers, J.; Franklin, J. P.; Maddison, D.; Awadelkareem, M. A.; Devine, M. J.; Koslover, E.; Avezov, E.

doi:10.1101/2025.10.06.677012

bioRxiv · 10.1101/2025.10.06.677012

Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates

Davi, V.·Parutto, P.·Crapart, C.·Zhang, Y.·Konno, T.·Chambers, J.·Franklin, J. P.·Maddison, D.·Awadelkareem, M. A.·Devine, M. J.·Koslover, E.·Avezov, E.

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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 Alzheimers 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 Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ERs capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalising ER dysfunction in neurodegeneration. This mechanism could apply universally to Ca2+-firing cells.

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Davi, V., Parutto, P., Crapart, C., Zhang, Y., Konno, T., Chambers, J., Franklin, J. P., Maddison, D., Awadelkareem, M. A., Devine, M. J., Koslover, E., Avezov, E.. 2025-10-07. Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates. https://doi.org/10.1101/2025.10.06.677012

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