Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

Francesco Matteo, Rebecca Bonrath, Veronica Pravata, Hanna Schmidt, Ane Cristina Ayo Martin, Rossella Giaimo, Danusa Menegaz, Stephan Riesenberg, Femke M. S. Vrij, Giuseppina Maccarrone, Maria Holzapfel, Tobias Straub, Steven A. Kushner, Stephen P. Robertson, Matthias Eder () and Silvia Cappello ()
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Francesco Matteo: Ludwig-Maximilians-University (LMU)
Rebecca Bonrath: Ludwig-Maximilians-University (LMU)
Veronica Pravata: Ludwig-Maximilians-University (LMU)
Hanna Schmidt: Max Planck Institute of Psychiatry
Ane Cristina Ayo Martin: International Max Planck Research School for Translational Psychiatry (IMPRS-TP)
Rossella Giaimo: Ludwig-Maximilians-University (LMU)
Danusa Menegaz: Max Planck Institute of Psychiatry
Stephan Riesenberg: Max Planck Institute for Evolutionary Anthropology
Femke M. S. Vrij: Erasmus MC University Medical Center
Giuseppina Maccarrone: Max Planck Institute of Psychiatry
Maria Holzapfel: Max Planck Institute of Psychiatry
Tobias Straub: Ludwig-Maximilians-University (LMU)
Steven A. Kushner: Erasmus MC University Medical Center
Stephen P. Robertson: University of Otago
Matthias Eder: Max Planck Institute of Psychiatry
Silvia Cappello: Ludwig-Maximilians-University (LMU)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Periventricular heterotopia (PH), a common form of gray matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 mimic PH features. However, neuronal activity in these 3D models has not yet been investigated. Here we show that silicon probe recordings reveal exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identify changes in neuronal morphology and synaptic function. Furthermore, patch-clamp recordings reveal a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Additional analyses reveal increased morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with rescue observed in DCHS1 neurons by wild-type DCHS1 expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of gray matter heterotopia.

Date: 2025
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DOI: 10.1038/s41467-025-56998-1

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