Format

Send to

Choose Destination
Cell Rep. 2014 Apr 10;7(1):1-11. doi: 10.1016/j.celrep.2014.03.019. Epub 2014 Apr 3.

Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons.

Author information

1
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
2
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.
3
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.
4
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; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Department of Neurology, University of Massachusetts Medical Center, Worcester, MA 01655, USA.
7
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
8
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; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The Howard Hughes Medical Institute. Electronic address: eggan@mcb.harvard.edu.
9
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: clifford.woolf@childrens.harvard.edu.

Abstract

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. SOD1(A4V/+) 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.

Comment in

PMID:
24703839
PMCID:
PMC4023477
DOI:
10.1016/j.celrep.2014.03.019
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Supplementary concept, Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center