SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids
- 1University of Calgary
Abstract
Dravet syndrome is a severe childhood neurological disorder caused mostly due to mutations in the sodium channel gene SCN1A. Although the disorder is widely attributed to dysfunction of inhibitory neurons, growing evidence suggests that disease mechanisms may begin much earlier during brain development. To investigate the developmental consequences of SCN1A haploinsufficiency, we generated patient-derived dorsal-ventral forebrain assembloids that model key features of human corticogenesis. We found that SCN1A was expressed in ventricular zone neural progenitors and that its reduced expression was associated with impaired growth, disrupted ventricular zone organization, and progressive depletion of progenitor populations. We further demonstrated reduced progenitor proliferation and self-renewal, accelerated cell-cycle exit, and premature neuronal differentiation, leading to increased production of excitatory neurons and enhanced network excitability. Single cell transcriptomic analyses revealed reduced cycling radial glial cells, accelerated progenitor maturation, and dysregulation of gap junction and calcium signaling pathways. Following these findings, we examined progenitor calcium activity and found that SCN1A haploinsufficiency disrupted coordinated functional network organization, resulting in reduced recurrent connectivity and fragmentation of functional cellular assemblies. These abnormalities occurred despite preserved intrinsic electrophysiological properties of individual progenitors, indicating a defect in population-level coordination rather than single cell electrophysiology. Together, our findings identify disrupted progenitor communication as an early developmental consequence of SCN1A haploinsufficiency and suggest that abnormalities within neural progenitor populations contribute to altered corticogenesis, excitatory neurogenesis, and circuit hyperexcitability in Dravet syndrome. This work expands current disease models beyond interneuron dysfunction and highlights the developing ventricular zone as a potential therapeutic target.
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BibTeX
@misc{dogra2026scn1a,
title = {{SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids}},
author = {D. Dogra and H. Fong and S. Zhang and T. Sumi and N. Rosin and N. Collao and M. Gordon and A. Korver and C. Gavrilovici and D. Noble and S. J. Guzman and L. Rohani and D. Rancourt and J. Biernaskie and J. Jacobs-Levan and R. Thompson and D. M. Kurrasch},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.14.758626},
url = {https://www.biorxiv.org/content/10.64898/2026.10.14.758626v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids
AU - D. Dogra
AU - H. Fong
AU - S. Zhang
AU - T. Sumi
AU - N. Rosin
AU - N. Collao
AU - M. Gordon
AU - A. Korver
AU - C. Gavrilovici
AU - D. Noble
AU - S. J. Guzman
AU - L. Rohani
AU - D. Rancourt
AU - J. Biernaskie
AU - J. Jacobs-Levan
AU - R. Thompson
AU - D. M. Kurrasch
PY - 2026
DA - 2026/10/14
PB - bioRxiv
DO - 10.64898/2026.10.14.758626
UR - https://www.biorxiv.org/content/10.64898/2026.10.14.758626v1
AB - Dravet syndrome is a severe childhood neurological disorder caused mostly due to mutations in the sodium channel gene SCN1A. Although the disorder is widely attributed to dysfunction of inhibitory neurons, growing evidence suggests that disease mechanisms may begin much earlier during brain development. To investigate the developmental consequences of SCN1A haploinsufficiency, we generated patient-derived dorsal-ventral forebrain assembloids that model key features of human corticogenesis. We found that SCN1A was expressed in ventricular zone neural progenitors and that its reduced expression was associated with impaired growth, disrupted ventricular zone organization, and progressive depletion of progenitor populations. We further demonstrated reduced progenitor proliferation and self-renewal, accelerated cell-cycle exit, and premature neuronal differentiation, leading to increased production of excitatory neurons and enhanced network excitability. Single cell transcriptomic analyses revealed reduced cycling radial glial cells, accelerated progenitor maturation, and dysregulation of gap junction and calcium signaling pathways. Following these findings, we examined progenitor calcium activity and found that SCN1A haploinsufficiency disrupted coordinated functional network organization, resulting in reduced recurrent connectivity and fragmentation of functional cellular assemblies. These abnormalities occurred despite preserved intrinsic electrophysiological properties of individual progenitors, indicating a defect in population-level coordination rather than single cell electrophysiology. Together, our findings identify disrupted progenitor communication as an early developmental consequence of SCN1A haploinsufficiency and suggest that abnormalities within neural progenitor populations contribute to altered corticogenesis, excitatory neurogenesis, and circuit hyperexcitability in Dravet syndrome. This work expands current disease models beyond interneuron dysfunction and highlights the developing ventricular zone as a potential therapeutic target.
ER -