Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

Francesco Di Matteo; Rebecca Bonrath; Veronica Pravata; Hanna Schmidt; Ane Cristina Ayo Martin; Rossella Di Giaimo; Danusa Menegaz; Stephan Riesenberg; Femke M.S. de Vrij; Giuseppina Maccarrone; Maria Holzapfel; Tobias Straub; Steven A. Kushner; Stephen P. Robertson; Matthias Eder; Silvia Cappello

doi:10.1038/s41467-025-56998-1

Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

Francesco Di Matteo, Rebecca Bonrath, Veronica Pravata, Hanna Schmidt, Ane Cristina Ayo Martin, Rossella Di Giaimo, Danusa Menegaz, Stephan Riesenberg, Femke M.S. de Vrij, Giuseppina Maccarrone, Maria Holzapfel, Tobias Straub, Steven A. Kushner, Stephen P. Robertson, Matthias Eder^*, Silvia Cappello^*

^*Corresponding author for this work

Psychiatry

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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.

Original language	English
Article number	1737
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-56998-1
Publication status	Published - 18 Feb 2025

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Publisher Copyright: © The Author(s) 2025.

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Di Matteo, F., Bonrath, R., Pravata, V., Schmidt, H., Ayo Martin, A. C., Di Giaimo, R., Menegaz, D., Riesenberg, S., de Vrij, F. M. S., Maccarrone, G., Holzapfel, M., Straub, T., Kushner, S. A., Robertson, S. P., Eder, M., & Cappello, S. (2025). Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia. Nature Communications, 16(1), Article 1737. https://doi.org/10.1038/s41467-025-56998-1

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title = "Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia",

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.",

author = "{Di Matteo}, Francesco and Rebecca Bonrath and Veronica Pravata and Hanna Schmidt and {Ayo Martin}, {Ane Cristina} and {Di Giaimo}, Rossella and Danusa Menegaz and Stephan Riesenberg and {de Vrij}, {Femke M.S.} and Giuseppina Maccarrone and Maria Holzapfel and Tobias Straub and Kushner, {Steven A.} and Robertson, {Stephen P.} and Matthias Eder and Silvia Cappello",

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Di Matteo, F, Bonrath, R, Pravata, V, Schmidt, H, Ayo Martin, AC, Di Giaimo, R, Menegaz, D, Riesenberg, S, de Vrij, FMS, Maccarrone, G, Holzapfel, M, Straub, T, Kushner, SA, Robertson, SP, Eder, M & Cappello, S 2025, 'Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia', Nature Communications, vol. 16, no. 1, 1737. https://doi.org/10.1038/s41467-025-56998-1

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T1 - Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

AU - Di Matteo, Francesco

AU - Bonrath, Rebecca

AU - Pravata, Veronica

AU - Schmidt, Hanna

AU - Ayo Martin, Ane Cristina

AU - Di Giaimo, Rossella

AU - Menegaz, Danusa

AU - Riesenberg, Stephan

AU - de Vrij, Femke M.S.

AU - Maccarrone, Giuseppina

AU - Holzapfel, Maria

AU - Straub, Tobias

AU - Kushner, Steven A.

AU - Robertson, Stephen P.

AU - Eder, Matthias

AU - Cappello, Silvia

PY - 2025/2/18

Y1 - 2025/2/18

N2 - 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.

AB - 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.

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VL - 16

JO - Nature Communications

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Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia

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