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Cell Stem Cell. 2014 Nov 6;15(5):559-73. doi: 10.1016/j.stem.2014.10.006. Epub 2014 Nov 6.

hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice.

Author information

1
Laboratory for Neural Reconstruction, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
2
Cellular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
3
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA; Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
4
MRC Electron and Light Microscopy Core Facility, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
5
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA; Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA. Electronic address: schung@mclean.harvard.edu.

Abstract

Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy.

PMID:
25517465
PMCID:
PMC4270101
DOI:
10.1016/j.stem.2014.10.006
[Indexed for MEDLINE]
Free PMC Article

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