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Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

Author

Listed:
  • Francesco Matteo

    (Ludwig-Maximilians-University (LMU)
    International Max Planck Research School for Translational Psychiatry (IMPRS-TP)
    Max Planck Institute of Psychiatry)

  • 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)
    Max Planck Institute of Psychiatry)

  • Rossella Giaimo

    (Ludwig-Maximilians-University (LMU)
    Max Planck Institute of Psychiatry
    University Federico II)

  • Danusa Menegaz

    (Max Planck Institute of Psychiatry)

  • Stephan Riesenberg

    (Max Planck Institute for Evolutionary Anthropology)

  • Femke M. S. Vrij

    (Erasmus MC University Medical Center
    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
    Columbia University Medical Center)

  • Stephen P. Robertson

    (University of Otago)

  • Matthias Eder

    (Max Planck Institute of Psychiatry)

  • Silvia Cappello

    (Ludwig-Maximilians-University (LMU)
    Max Planck Institute of Psychiatry)

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.

Suggested Citation

  • Francesco Matteo & Rebecca Bonrath & Veronica Pravata & Hanna Schmidt & Ane Cristina Ayo Martin & Rossella Giaimo & Danusa Menegaz & Stephan Riesenberg & Femke M. S. Vrij & Giuseppina Maccarrone & Mar, 2025. "Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56998-1
    DOI: 10.1038/s41467-025-56998-1
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    1. Giorgia Quadrato & Tuan Nguyen & Evan Z. Macosko & John L. Sherwood & Sung Min Yang & Daniel R. Berger & Natalie Maria & Jorg Scholvin & Melissa Goldman & Justin P. Kinney & Edward S. Boyden & Jeff W., 2017. "Cell diversity and network dynamics in photosensitive human brain organoids," Nature, Nature, vol. 545(7652), pages 48-53, May.
    2. Christina Kyrousi & Adam C. O’Neill & Agnieska Brazovskaja & Zhisong He & Pavel Kielkowski & Laure Coquand & Rossella Giaimo & Pierpaolo D’ Andrea & Alexander Belka & Andrea Forero Echeverry & Davide , 2021. "Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
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