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

Abstract

Dravet syndrome (DS) is a severe pediatric epilepsy primarily caused by de novo mutation in the SCN1A gene encoding the alpha subunit of the voltage-gated sodium channel. While early in vivo studies linked DS pathology to GABAergic disinhibition, recent studies report altered sodium currents in both inhibitory and excitatory neurons. In vitro models containing both neuronal subtypes may offer deeper insights into functionality of neuronal networks. This study examined the effects of two different SCN1A pathogenic variants on the functional phenotype of human induced pluripotent stem cell -derived enriched GABAergic cultures and heterogeneous GABA- and glutamatergic cultures using microelectrode arrays. We observed functional differences evident as increased network bursts in one DS patient line compared to controls and to another DS patient line in GABAergic and heterogenous cultures. Importantly, heterogeneous cultures revealed lower spiking and bursting frequency in both DS patient lines. Principal component analysis confirmed distinct clustering of the functional profiles of the DS patient and control networks in heterogeneous cultures. The magnitude of the altered functional activity reflected the clinical severity of the disease. Thus, functional alterations caused by SCN1A variants are apparent in heterogenous cultures indicating their competence for characterizing disease phenotypes in DS.