Pluripotent stem cell-derived interneuron progenitors mature and restore memory deficits but do not suppress seizures in the epileptic mouse brain

Nickesha C Anderson; Meghan A Van Zandt; Swechhya Shrestha; Daniel B Lawrence; Jyoti Gupta; Christopher Y Chen; Felicia A Harrsch; Trinithas Boyi; Carolyn E Dundes; Gloster Aaron; Janice R Naegele; Laura Grabel

doi:10.1016/j.scr.2018.10.007

Pluripotent stem cell-derived interneuron progenitors mature and restore memory deficits but do not suppress seizures in the epileptic mouse brain

Stem Cell Res. 2018 Dec:33:83-94. doi: 10.1016/j.scr.2018.10.007. Epub 2018 Oct 5.

Authors

Affiliations

¹ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: ncanderson@wesleyan.edu.
² Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: mvanzandt@wesleyan.edu.
³ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: sshrestha@wesleyan.edu.
⁴ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA; Program in Neuroscience and Behavior, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: dblawrence@wesleyan.edu.
⁵ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: jgupta@wesleyan.edu.
⁶ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: cychen@wesleyan.edu.
⁷ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA.
⁸ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA; Program in Neuroscience and Behavior, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: tboyi@wesleyan.edu.
⁹ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: cdundes@stanford.edu.
¹⁰ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA; Program in Neuroscience and Behavior, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: gaaron@wesleyan.edu.
¹¹ Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA; Program in Neuroscience and Behavior, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: jnaegele@wesleyan.edu.
¹² Dept. of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT 06459, USA. Electronic address: lgrabel@wesleyan.edu.

PMID: 30340090
DOI: 10.1016/j.scr.2018.10.007

Abstract

GABAergic interneuron dysfunction has been implicated in temporal lobe epilepsy (TLE), autism, and schizophrenia. Inhibitory interneuron progenitors transplanted into the hippocampus of rodents with TLE provide varying degrees of seizure suppression. We investigated whether human embryonic stem cell (hESC)-derived interneuron progenitors (hESNPs) could differentiate, correct hippocampal-dependent spatial memory deficits, and suppress seizures in a pilocarpine-induced TLE mouse model. We found that transplanted ventralized hESNPs differentiated into mature GABAergic interneurons and became electrophysiologically active with mature firing patterns. Some mice developed hESNP-derived tumor-like NSC clusters. Mice with transplants showed significant improvement in the Morris water maze test, but transplants did not suppress seizures. The limited effects of the human GABAergic interneuron progenitor grafts may be due to cell type heterogeneity within the transplants.

Keywords: Electrophysiological analyses; Embryonic stem cells; GABAergic interneuron progenitors; Hippocampal-dependent spatial memory; Temporal lobe epilepsy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Disease Models, Animal
Epilepsy, Temporal Lobe / complications*
Female
Humans
Interneurons / metabolism*
Male
Memory Disorders / etiology*
Memory Disorders / pathology
Mice
Pluripotent Stem Cells / metabolism*
Seizures / etiology*
Seizures / pathology