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bioRxiv · 10.1101/2025.01.28.635170

The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis

Uy, J. A.·Dargaei, Z.·Geahchan, S.·Botler, L.·Pan, Y.·Brown, C. O.·Howe, J. L.·Scherer, S. W.·Bains, J. S.·Singh, K. K.
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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.

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Uy, J. A., Dargaei, Z., Geahchan, S., Botler, L., Pan, Y., Brown, C. O., Howe, J. L., Scherer, S. W., Bains, J. S., Singh, K. K.. 2025-01-28. The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis. https://doi.org/10.1101/2025.01.28.635170

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