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

Miles Cunningham; Jun-Hyeong Cho; Amanda Leung; George Savvidis; Sandra Ahn; Minho Moon; Paula K J Lee; Jason J Han; Nima Azimi; Kwang-Soo Kim; Vadim Y Bolshakov; Sangmi Chung

doi:10.1016/j.stem.2014.10.006

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

Journal article

Open access

Peer reviewed

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

Miles Cunningham, Jun-Hyeong Cho, Amanda Leung, George Savvidis, Sandra Ahn, Minho Moon, Paula K J Lee, Jason J Han, Nima Azimi, Kwang-Soo Kim, …

Cell stem cell, Vol.15(5), pp.559-573

11/06/2014

DOI: 10.1016/j.stem.2014.10.006

PMCID: PMC4270101

PMID: 25517465

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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.

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

Details

Title: Subtitle: hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice
Creators: Miles Cunningham - McLean Hospital
Jun-Hyeong Cho - McLean Hospital
Amanda Leung - McLean Hospital
George Savvidis - McLean Hospital
Sandra Ahn - McLean Hospital
Minho Moon - McLean Hospital
Paula K J Lee - McLean Hospital
Jason J Han - McLean Hospital
Nima Azimi - McLean Hospital
Kwang-Soo Kim - McLean Hospital
Vadim Y Bolshakov - McLean Hospital
Sangmi Chung - McLean Hospital
Resource Type: Journal article
Publication Details: Cell stem cell, Vol.15(5), pp.559-573
DOI: 10.1016/j.stem.2014.10.006
PMID: 25517465
PMCID: PMC4270101
NLM abbreviation: Cell Stem Cell
ISSN: 1934-5909
eISSN: 1875-9777
Grant note: R01 NS070577 / NINDS NIH HHS MH090464 / NIMH NIH HHS R21 NS079977 / NINDS NIH HHS R01 MH090464 / NIMH NIH HHS NS070577 / NINDS NIH HHS NS079977 / NINDS NIH HHS
Language: English
Date published: 11/06/2014
Academic Unit: Neurology
Record Identifier: 9984302203502771

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