Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
Brian J. Wainger,
Evangelos Kiskinis,
Cassidy Mellin,
Ole Wiskow,
Steve S.W. Han,
Jackson Sandoe,
Numa P. Perez,
Luis A. Williams,
Seungkyu Lee,
Gabriella Boulting,
James D. Berry,
Robert H. Brown Jr.,
Merit E. Cudkowicz,
Bruce P. Bean,
Kevin Eggan,
Clifford J. Woolf
Affiliations
Brian J. Wainger
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Evangelos Kiskinis
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Cassidy Mellin
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Ole Wiskow
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Steve S.W. Han
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Jackson Sandoe
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Numa P. Perez
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Luis A. Williams
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Seungkyu Lee
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Gabriella Boulting
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
James D. Berry
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Robert H. Brown Jr.
Department of Neurology, University of Massachusetts Medical Center, Worcester, MA 01655, USA
Merit E. Cudkowicz
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Bruce P. Bean
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kevin Eggan
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Clifford J. Woolf
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.
