Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity

Jin Chong Xu, Jing Fan, Xueqing Wang, Stephen M. Eacker, Tae In Kam, Li Chen, Xiling Yin, Juehua Zhu, Zhikai Chi, Haisong Jiang, Rong Chen, Ted M. Dawson, Valina L. Dawson

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1+ neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

Original languageEnglish (US)
Article numberra48
JournalScience Translational Medicine
Volume8
Issue number333
DOIs
StatePublished - Apr 6 2016
Externally publishedYes

Fingerprint

Interneurons
Cell Death
Neurons
Pluripotent Stem Cells
Poly(ADP-ribose) Polymerases
Tretinoin
N-Methyl-D-Aspartate Receptors
Nitric Oxide
Ischemia
Animal Models
Clinical Trials
Apoptosis
Oxygen
Glucose
Population
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. / Xu, Jin Chong; Fan, Jing; Wang, Xueqing; Eacker, Stephen M.; Kam, Tae In; Chen, Li; Yin, Xiling; Zhu, Juehua; Chi, Zhikai; Jiang, Haisong; Chen, Rong; Dawson, Ted M.; Dawson, Valina L.

In: Science Translational Medicine, Vol. 8, No. 333, ra48, 06.04.2016.

Research output: Contribution to journalArticle

Xu, JC, Fan, J, Wang, X, Eacker, SM, Kam, TI, Chen, L, Yin, X, Zhu, J, Chi, Z, Jiang, H, Chen, R, Dawson, TM & Dawson, VL 2016, 'Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity', Science Translational Medicine, vol. 8, no. 333, ra48. https://doi.org/10.1126/scitranslmed.aad0623
Xu, Jin Chong ; Fan, Jing ; Wang, Xueqing ; Eacker, Stephen M. ; Kam, Tae In ; Chen, Li ; Yin, Xiling ; Zhu, Juehua ; Chi, Zhikai ; Jiang, Haisong ; Chen, Rong ; Dawson, Ted M. ; Dawson, Valina L. / Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. In: Science Translational Medicine. 2016 ; Vol. 8, No. 333.
@article{c9c24cfd483f4f0cbefc82c78aa77cca,
title = "Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity",
abstract = "Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1+ neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.",
author = "Xu, {Jin Chong} and Jing Fan and Xueqing Wang and Eacker, {Stephen M.} and Kam, {Tae In} and Li Chen and Xiling Yin and Juehua Zhu and Zhikai Chi and Haisong Jiang and Rong Chen and Dawson, {Ted M.} and Dawson, {Valina L.}",
year = "2016",
month = "4",
day = "6",
doi = "10.1126/scitranslmed.aad0623",
language = "English (US)",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "333",

}

TY - JOUR

T1 - Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity

AU - Xu, Jin Chong

AU - Fan, Jing

AU - Wang, Xueqing

AU - Eacker, Stephen M.

AU - Kam, Tae In

AU - Chen, Li

AU - Yin, Xiling

AU - Zhu, Juehua

AU - Chi, Zhikai

AU - Jiang, Haisong

AU - Chen, Rong

AU - Dawson, Ted M.

AU - Dawson, Valina L.

PY - 2016/4/6

Y1 - 2016/4/6

N2 - Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1+ neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

AB - Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1+ neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

UR - http://www.scopus.com/inward/record.url?scp=84963623377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84963623377&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aad0623

DO - 10.1126/scitranslmed.aad0623

M3 - Article

C2 - 27053772

AN - SCOPUS:84963623377

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 333

M1 - ra48

ER -