Cerebral Organoids Uncover Mechanisms of Neural Activity Changes in Epileptogenesis
Year: 2025
Type: preprint
Abstract: Neurological disorders often originate from progressive brain network dysfunctions that start years before symptoms appear. How these changes emerge in the developing human brain remains elusive due to a lack of tractable model systems. Here, we show a cerebral organoid model of Tuberous Sclerosis Complex (TSC) that recapitulates hallmarks of epileptogenesis in vitro. We compare extracellular recordings of TSC organoids with intraoperative electrocorticography from TSC patients to reveal striking functional similarities, including high-frequency oscillations - an electrical biomarker for epileptogenic tissue. In TSC, a human-specific interneuron sub-type derived from the caudal ganglionic eminence drives network hyper-synchronization through increased spontaneous firing and altered excitability. Inhibiting overproliferation of its progenitors via long-term epidermal growth factor receptor inhibition prevented the onset of this pathological phenotype at functional and morphological levels. Our work shows that organoids allow mechanistic analysis of emerging neural network phenotypes, enabling anti-epileptogenic drug testing in a human brain development model.
Authors: Sakurako Nagumo Wong, Michael Zabolocki, Oliver L. Eichmüller, Maryse A van ‘t Klooster, Marthe M. Priouret, Christian Krauditsch, Simone Krautberger, Julia Chu, Susana González-Granero, Lucas Barea Moya, Charles Fieseler, Segundo Jose Guzman, Daniel Reumann, Ramsey Najm, Jose Manuel García Verdugo, Mercedes F. Paredes, Manuel Zimmer, Maeike Zijlmans, Peter Jonas, Cedric Bardy, Nina Corsini, Jürgen A. Knoblich
Institutions: Institute of Molecular Biotechnology, Austrian Academy of Sciences, University Medical Center Utrecht, University of California, San Francisco, Universitat de València, Biomedical Research Networking Center on Neurodegenerative Diseases, University of Vienna, Institute of Science and Technology Austria, Flinders University
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4413805029