The more, the better: modeling dravet syndrome with induced pluripotent stem cell-derived neurons.

Commentary Advances in cellular reprogramming have made it possible to generate virtually any cell type from pluripotent stem cells. Initially, embryonic stem cells were the only source of truly plu-ripotent cells. However, in 2007, it was reported that induced pluripotent stem cells (iPSCs) could be generated from human somatic cells (1, 2). This discovery enabled iPSCs generated from patients to be used as an in vitro model for studying disease mechanisms and testing therapeutics. Patient cells obtained from skin biopsy can be reprogrammed to pluripotency by addition of the four factors: Oct3/4, Sox2, Klf4, and cMYC (1). These iPSCs have infinite capacity for self-renewal and are pluripotent, making them an unlimited resource for differentiating any cell type for experimental studies. iPSCs provide a particularly attractive model for neurologic disease, where access to live human tissue suitable for culture is extremely limited. In this study, Liu and colleagues generated iPSC-derived neurons to model Dravet syndrome, a catastrophic, infant-onset epileptic encephalopathy with pharmacoresistant seizures, developmental regression, and increased mortality (3). In over 80% of patients, Dravet syndrome is caused by heterozygous mutation of SCN1A, which encodes the voltage-gated sodium channel Nav1.1 (4). Most Dravet syndrome mutations result in loss of Nav1.1 function, suggesting that SCN1A is haploinsufficient. Initially, it was puzzling that loss of a voltage-gated sodium channel, which underlies action potentials , could lead to hyperexcitability. However, results from mice with targeted deletion of Scn1a or from mice engineered with a human nonsense mutation suggested that loss of Nav1.1 predominantly affected GABAergic inhibitory neurons (5, 6). These observations led to the hypothesis that Dravet syndrome is an " interneuronopathy, " with hyperexcitability and seizures resulting from loss of inhibitory input onto excitatory principal neurons (pyramidal cells). Liu and colleagues sought to determine the effects of SCN1A mutations on human neuronal function using iPSC-derived neurons from Dravet syndrome patients. They generated iPSCs from three unaffected controls and two patients, OBJECTIVE: Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage-gated sodium channel Na v 1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that …