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Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism

Authors

  • Yu Liu MD, PhD,

    1. Departments of Neurology, University of Michigan Medical Center, Ann Arbor, MI
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  • Luis F. Lopez-Santiago PhD,

    1. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
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  • Yukun Yuan PhD,

    1. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
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  • Julie M. Jones MS,

    1. Human Genetics, University of Michigan Medical Center, Ann Arbor, MI
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  • Helen Zhang MS,

    1. Departments of Neurology, University of Michigan Medical Center, Ann Arbor, MI
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  • Heather A. O'Malley PhD,

    1. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
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  • Gustavo A. Patino PhD,

    1. Departments of Neurology, University of Michigan Medical Center, Ann Arbor, MI
    2. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
    3. Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, MI
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  • Janelle E. O'Brien PhD,

    1. Human Genetics, University of Michigan Medical Center, Ann Arbor, MI
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  • Raffaella Rusconi PhD,

    1. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
    Current affiliation:
    1. German Center for Neurodegenerative Disease, Bonn, Germany
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  • Ajay Gupta MD,

    1. Neurological Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH
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  • Robert C. Thompson PhD,

    1. Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, MI
    2. Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, MI
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  • Marvin R. Natowicz MD, PhD,

    1. Neurological Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH
    2. Genomic Medicine, Cleveland Clinic, Cleveland, OH
    3. Pediatric, Cleveland Clinic, Cleveland, OH
    4. Pathology and Laboratory Medicine Institutes, Cleveland Clinic, Cleveland, OH
    5. Lerner College of Medicine, Cleveland Clinic, Cleveland, OH
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  • Miriam H. Meisler PhD,

    1. Human Genetics, University of Michigan Medical Center, Ann Arbor, MI
    2. Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, MI
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  • Lori L. Isom PhD,

    1. Pharmacology, University of Michigan Medical Center, Ann Arbor, MI
    2. Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, MI
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  • Jack M. Parent MD

    Corresponding author
    1. Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, MI
    2. VA Ann Arbor Healthcare System, Ann Arbor, MI
    • Departments of Neurology, University of Michigan Medical Center, Ann Arbor, MI
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Errata

This article is corrected by:

  1. Errata: Erratum Volume 78, Issue 5, 838, Article first published online: 24 October 2015

Address correspondence to Dr Parent, 5021 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail: parent@umich.eduCurrent address for Dr Rusconi: German Center for Neurodegenerative Disease, Bonn, Germany.

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 Nav1.1. 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 Nav1.1 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. Ann Neurol 2013;74:128–139

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