Abnormalities in the functional activity of neural networks in a human iPSC model of Dravet syndrome

Dravet syndrome (DS) is a severe pediatric epilepsy with a limited response to current antiseizure medications. Majority of DS cases are caused by a de novo mutation in the SCN1A gene, encoding the alpha subunit of the voltage-gated sodium channel. While early in vivo studies have shown that DS pathology results from the disinhibition of GABAergic inhibitory neurons, recent studies report alterations in sodium currents in both excitatory and inhibitory neurons. Investigating the excitatory-inhibitory interplay is essential for elucidating the functional alterations caused by SCN1A mutations. Here, the aim was to study how different SCN1A gene pathogenic variants affect the functional phenotype of DS human induced pluripotent stem cell-derived neuronal networks in enriched GABAergic cultures and heterogeneous glutamatergic and GABAergic cultures, using microelectrode arrays (MEAs). We report functional differences in patient-derived GABAergic cultures. In heterogeneous cultures, DS patient-derived neurons displayed altered activity with prominent network bursts and overall, the altered functional activity correlated with the clinical severity of the disease. Principal component analysis revealed distinct clustering between the DS patient and control heterogeneous cultures. Thus, pathogenic SCN1A variants alter the neuronal network functionality suggesting that heterogeneous cultures are competent physiological models for characterizing disease phenotype alterations in DS using MEAs.