title: hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice.
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.
authors.affiliation: Laboratory for Neural Reconstruction, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Miles
authors.initials: M
authors.lastname: Cunningham
authors.affiliation: Cellular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Jun-Hyeong
authors.initials: JH
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Amanda
authors.initials: A
authors.lastname: Leung
authors.affiliation: 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.
authors.forename: George
authors.initials: G
authors.lastname: Savvidis
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ahn
authors.affiliation: 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.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: 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.
authors.forename: Paula K J
authors.initials: PK
authors.lastname: Lee
authors.affiliation: MRC Electron and Light Microscopy Core Facility, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Han
authors.affiliation: Laboratory for Neural Reconstruction, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Azimi
authors.affiliation: 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.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Cellular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Bolshakov
authors.affiliation: 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.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Chung
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation; D002465:Cell Movement; D005260:Female; D059330:GABAergic Neurons / Q000166:cytology / Q000637:transplantation* / Q000648:ultrastructure; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007395:Interneurons / Q000166:cytology / Q000637:transplantation* / Q000648:ultrastructure; D008297:Male; D008473:Median Eminence / Q000166:cytology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009433:Neural Inhibition; D062308:Optogenetics; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012640:Seizures / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation; D055366:Synaptic Potentials