Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia
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.
Authors
- Rebecca Bonrath (ORCID: https://orcid.org/0000-0001-9242-7615)
- Femke M.S. de Vrij (ORCID: https://orcid.org/0000-0003-0825-3806)
- Stephen P. Robertson (ORCID: https://orcid.org/0000-0002-5181-7809)
- Francesco Di Matteo
- Maria Holzapfel
- Steven A. Kushner (ORCID: https://orcid.org/0000-0002-9777-3338)
- Rossella Di Giaimo (ORCID: https://orcid.org/0000-0003-3604-3697)
- Stephan Riesenberg (ORCID: https://orcid.org/0000-0001-8171-1717)
- Matthias Eder (ORCID: https://orcid.org/0000-0002-2579-2628)
- Silvia Cappello (ORCID: https://orcid.org/0000-0003-1553-6775)
- Tobias Straub (ORCID: https://orcid.org/0000-0002-0547-0453)
- Veronica M. Pravatà (ORCID: https://orcid.org/0000-0002-0081-9310)
- Giuseppina Maccarrone
- Hanna Schmidt
- Ane Cristina Ayo Martin
- Danusa Menegaz
Institutions
- Columbia University Irving Medical Center (US)
- Erasmus MC (NL)
- Federico II University Hospital (IT)
- Max Planck Institute for Evolutionary Anthropology (DE)
- Max Planck Institute of Psychiatry (DE)
- University of Otago (NZ)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1038/s41467-025-56998-1
- Citations
- 5
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- E-Rare
- European Commission
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Max-Planck-Gesellschaft
- Ludwig-Maximilians-Universität München