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

Abstract

AbstractSCN1Aencodes 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 causeSCN1Aloss-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 fromSCN1ADS 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 3Din vitromodel to reveal the cellular mechanisms of DS and predict drug response. In summary, our patient iPSC-derived neuronal model ofSCN1ADS 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.