The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis

The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD). The expression pattern of SCN2A begins during fetal 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 (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity.