Year: 2013
Type: article
Abstract: 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 decreased Na(v) 1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient-specific neurons. METHODS: Here we derive forebrain-like pyramidal- and bipolar-shaped neurons from 2 DS subjects and 3 human controls by iPSC reprogramming of fibroblasts. DS and control iPSC-derived neurons are compared using whole-cell patch clamp recordings. Sodium current density and intrinsic neuronal excitability are examined. RESULTS: Neural progenitors from DS and human control iPSCs display a forebrain identity and differentiate into bipolar- and pyramidal-shaped neurons. DS patient-derived neurons show increased sodium currents in both bipolar- and pyramidal-shaped neurons. Consistent with increased sodium currents, both types of patient-derived neurons show spontaneous bursting and other evidence of hyperexcitability. Sodium channel transcripts are not elevated, consistent with a post-translational mechanism. INTERPRETATION: These data demonstrate that epilepsy patient-specific iPSC-derived neurons are useful for modeling epileptic-like hyperactivity. Our findings reveal a previously unrecognized cell-autonomous epilepsy mechanism potentially underlying DS, and offer a platform for screening new antiepileptic therapies.
Source: Annals of Neurology
DOI: 10.1002/ana.23897
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Epilepsy Society, Epilepsy Foundation, University of Michigan, Epilepsy Society, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Role of Sodium Channel SCN1B in Inherited Epilepsy, Sodium Channel Beta Subunit Cell Adhesive Interactions, Molecular Control of Na+ Channel Density and Localization in Myelinated Axons, Michigan Predoctoral Training in Genetics, G3594001241, G3736803298, G4661265727, Neural Progenitor Grafting for Restorative Stroke Therapy, Role of SCN1B in Inherited Epilepsy, Stem cell derived neurons and inherited epilepsy, PREDICTIVE GENES, MECHANISMS, AND CLINICAL BIOMARKERS OF SUDEP, G8732851150, Role of Sodium Channel SCN1B in Inherited Epilepsy, G9000215422, Functional Genetics of the Neuronal Sodium Channel Gene SCN8A, Multidisciplinary Cardiovascular Research Training
OpenAlex ID: W2162587549