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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal*
  • Cell Differentiation
  • Cell Movement
  • Female
  • GABAergic Neurons / cytology
  • GABAergic Neurons / transplantation*
  • GABAergic Neurons / ultrastructure
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Interneurons / cytology
  • Interneurons / transplantation*
  • Interneurons / ultrastructure
  • Male
  • Median Eminence / cytology
  • Mice, Inbred NOD
  • Mice, SCID
  • Neural Inhibition
  • Optogenetics
  • Pluripotent Stem Cells / cytology*
  • Seizures / pathology
  • Seizures / physiopathology
  • Seizures / therapy*
  • Stem Cell Transplantation*
  • Synaptic Potentials