Skip to content
DraconiticResearch
Search Sources API
220,616 studies31 sourcesUpdated 22 min ago
Peer-reviewedCC BY-NC-NDNature communications

The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis.

  • Jarryll A Uy1,2
  • Zahra Dargaei2
  • Sarah Geahchan1,2
  • Laura Botler1,2
  • Yi Pan2
  • Chad O Brown2
  • Jennifer L Howe3
  • Stephen W Scherer3,4,5
  • Jaideep S Bains2
  • Karun K Singh6,7
7 affiliations
  1. 1Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  2. 2Krembil Research Institute, University Health Network, Toronto, ON, Canada.
  3. 3The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
  4. 4Sick Kids Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
  5. 5Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  6. 6Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [email protected].
  7. 7Krembil Research Institute, University Health Network, Toronto, ON, Canada. [email protected].
Read full textPDFDOICite

Abstract

Voltage-gated sodium channels regulate neuronal excitability and synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD) and a broad spectrum of epilepsy phenotypes, including early-onset developmental and epileptic encephalopathies. The expression pattern of SCN2A begins during prenatal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated Sonic hedgehog signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to Nav1.2-dependent sodium channel dysfunction and reduced action potential generation, leading to abnormal neuronal network activity. Our results identify a mechanism for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precede postnatal neural circuit dysfunction in SCN2A-associated disorders.

Related

  1. Thalamic NRXN1-mediated input to human cortical progenitors drives excitatory neurogenesis
    Claudia V. Nguyen, Antoni Martija, Daniel C. Jaklic +15
    Science (New York, N.Y.)Peer-reviewedLicence not statedFull text2 citedNeurosciencePMC
  2. An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure
    V. Serra, F. Brandalise, V. Miczan +2
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  3. Two-State Effective Connectivity Predicts the effect of Anterior Cingulate Cortex Excitatory / Inhibitory Balance on Posterior Cingulate Cortex
    A. Asadpour, A. Malaviya, J. Cook +4
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  4. The role of mu opioid receptors on excitatory and inhibitory neurons in the rostral ventromedial medulla in neuropathic pain
    J. C. Moffa, A. Gao, V. Kalyanaraman +2
    bioRxivPreprintCC BY-NCFull textNeurosciencebioRxiv
  5. Differential excitatory-inhibitory balance within dorsolateral prefrontal cortex links inter-network interactions in working memory
    Zihang Xu, Haiqi Zhu, Yangping Li +5
    Communications BiologyPeer-reviewedCC BY 4.0Full textNeuroscienceCrossref

Cite

BibTeXRIS
BibTeX
@article{uy2026sodium,
  title = {{The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis.}},
  author = {Jarryll A Uy and Zahra Dargaei and Sarah Geahchan and Laura Botler and Yi Pan and Chad O Brown and Jennifer L Howe and Stephen W Scherer and Jaideep S Bains and Karun K Singh},
  journal = {Nature communications},
  year = {2026},
  month = jul,
  doi = {10.1038/s41467-026-75751-w},
  url = {https://europepmc.org/article/MED/43009472},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis.
AU  - Jarryll A Uy
AU  - Zahra Dargaei
AU  - Sarah Geahchan
AU  - Laura Botler
AU  - Yi Pan
AU  - Chad O Brown
AU  - Jennifer L Howe
AU  - Stephen W Scherer
AU  - Jaideep S Bains
AU  - Karun K Singh
PY  - 2026
DA  - 2026/07/27
JO  - Nature communications
DO  - 10.1038/s41467-026-75751-w
UR  - https://europepmc.org/article/MED/43009472
AB  - Voltage-gated sodium channels regulate neuronal excitability and synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD) and a broad spectrum of epilepsy phenotypes, including early-onset developmental and epileptic encephalopathies. The expression pattern of SCN2A begins during prenatal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated Sonic hedgehog signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to Nav1.2-dependent sodium channel dysfunction and reduced action potential generation, leading to abnormal neuronal network activity. Our results identify a mechanism for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precede postnatal neural circuit dysfunction in SCN2A-associated disorders.
SN  - 2041-1723
ER  -