SCN1A channelopathies: Navigating from genotype to neural circuit dysfunction

The SCN1A gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na(V)1.1 within inhibitory interneurons. The phenotype of SCN1A disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability. However, recent studies have identified SCN1A gain-of-function variants associated with epilepsy, and the presence of cellular and synaptic changes in mouse models that point toward homeostatic adaptations and complex network remodeling. These findings highlight the need to understand microcircuit-scale dysfunction in SCN1A disorders to contextualize genetic and cellular disease mechanisms. Targeting the restoration of microcircuit properties may be a fruitful strategy for the development of novel therapies.