Neuronal channelopathies cause various brain disorders including epilepsy, migraine and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders are poorly understood. One particularly devastating channelopathy is Dravet Syndrome (DS), a severe childhood epileptic encephalopathy with a high risk of Sudden Unexplained Death in Epilepsy (SUDEP). DS is typically caused by de novo dominant mutations in SCN1A, encoding the voltage-gated Na+ channel Nav1.1. Although SUDEP is the most devastating consequence of epilepsy and the leading cause of epilepsy mortality, astonishingly little is understood about its causes and no biomarkers exist to identify at risk epilepsy patients. Heterologous expression of mutant Nav1.1 channels suggests haploinsufficiency, raising the question of how loss of sodium channels underlying action potentials produces hyperexcitability. Data from DS mouse models indicate both decreased Na+ current in interneurons, implicating disinhibition, and increased Na+ current in pyramidal cells, implicating hyperexcitability, depending on genetic background, brain area, and animal age. To understand the effects of SCN1A DS mutations in human neurons we derived forebrain-like neurons from two DS subjects by induced pluripotent stem cell (iPSC) reprogramming of patient fibroblasts and compared them with iPSC-derived neurons from human controls. We found that DS patient-derived neurons have increased Na+ current density in both bipolar- and pyramidal-shaped neurons. Consistent with increased Na+ current, both putative excitatory and inhibitory patient-derived neurons showed spontaneous bursting and other evidence of hyperexcitability. Our data provided some of the first evidence that epilepsy patient-specific neurons obtained via the iPSC method are useful for modeling epileptic-like hyperactivity. Because NaV1.1 is also expressed in heart, a compelling idea is that altered sodium currents in DS cardiac myocytes, in addition to central neurons, may lead to arrhythmias and contribute to SUDEP. To test this hypothesis, we used the iPSC method to derive cardiac myocytes from fibroblasts of DS subjects. Our data suggest that a subset of DS subjects shows abnormal cardiac myoycte sodium currents and excitability. In parallel studies of a DS human mutant SCN1A knock-in mouse model, we observed spontaneous seizures and SUDEP in the mice, increased ventricular CM sodium current density, and ventricular arrhythmias at the time of SUDEP. The goal of our work is to provide a greater understanding of the mechanisms of DS and related diseases that may lead to novel therapeutic agents for epilepsy.

<strong>About the Speakers</strong>
Lori Isom, Ph.D. and Jack Parent, M.D. are scientific leaders in understanding the role of mutations in ion channels in epilepsy. They are also co-leaders of the National Institute of Neurological Diseases and Stroke funded “Center Without Walls” that is designed to investigate sudden death in epilepsy (SUDEP), the most devastating complication of the disorder.