Abstract SCN1A encodes Naᵥ1.1, a voltage-gated sodium channel preferentially expressed in GABAergic interneurons, and it is the major cause of Dravet Syndrome (DS), a rare condition of developmental and epileptic encephalopathy (DEE). Among over 1000 DS mutations reported to date, almost all cause SCN1A loss-of function (LoF). A reduction in NaV1.1 function in inhibitory neurons would subsequently cause an over-excitation of glutamatergic neurons resulting in seizures, which are exacerbated by the use of sodium channel blocking common anti-seizure medications (ASM). In this study we generated and assessed 3D spheroids enriched with GABAergic neurons from SCN1A DS patient to establish a 3D human-derived DS model. To investigate developmental disruptions in DS pathophysiology we profiled the transcriptome of patient-derived spheroids and subsequently, tested the capability of this 3D in vitro model to reveal the cellular mechanisms of DS and predict drug response. In summary, our patient iPSC-derived neuronal model of SCN1A DS revealed a profound dysregulation of developmental processes which correlated with functional disruption in GABAergic neurons and predicted response to fenfluramine, an ASM increasingly used for the treatment of DS.

Emerging neurodevelopmental mechanisms in patient induced pluripotent stem cells-derived spheroids modellingSCN1ADravet Syndrome