Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons

Matthew R. Livesey; Bilada Bilican; Jing Qiu; Nina Marie Rzechorzek; Ghazal Haghi; Karen Burr; Giles E. Hardingham; Siddharthan Chandran; David J. A. Wyllie

doi:10.1523/JNEUROSCI.5410-13.2014

Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons

Matthew R. Livesey, Bilada Bilican, Jing Qiu, Nina Marie Rzechorzek, Ghazal Haghi, Karen Burr, Giles E. Hardingham, Siddharthan Chandran^*, David J. A. Wyllie

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes in AMPAR composition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl(-) levels, which determines the reversal potential of GABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential, human stem-cell-derived neurons represent a valuable tool for studying these fundamental properties.

Original language	English
Pages (from-to)	4070-4075
Number of pages	6
Journal	Journal of Neuroscience
Volume	34
Issue number	11
DOIs	https://doi.org/10.1523/JNEUROSCI.5410-13.2014
Publication status	Published - 12 Mar 2014

Keywords / Materials (for Non-textual outputs)

GABA
glutamate
neurotransmitter
patch clamp
qRT-PCR
stem cells
PLURIPOTENT STEM-CELLS
RECEPTOR SUBUNIT EXPRESSION
RAT HIPPOCAMPAL-NEURONS
CEREBRAL WHITE-MATTER
DEVELOPMENTAL REGULATION
REGIONAL SUSCEPTIBILITY
HYPOXIC/ISCHEMIC INJURY
CORTEX
FOREBRAIN
BRAIN

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10.1523/JNEUROSCI.5410-13.2014

4070.full
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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F/SHIP: MISS NINA M RZECHORZEK - USING STEM CELLS TO STUDY NEURONAL-GLIAL INTERACTION IN NEURODEGENERATIVE DISEASE MODELS: THE GLIAL ENVIRONMENT AND NON-CELL-AUTONOMOUS MECHANISMS OF NEURODEGENERATION
Chandran, S. (Principal Investigator) & Rzechorzek, N. (Researcher)
UK-based charities
23/01/12 → 22/01/19
Project: Research
Receptors, Function and plasticity in human embryonic stem cell-derived neurons.
Ffrench-Constant, C. (Principal Investigator)
UK-based charities
10/01/11 → 9/01/15
Project: Research
FELLOWSHIP: Control of neuroprotection through NMDA receptor dependant regulation of antioxidant status.
Hardingham, G. (Principal Investigator)
MRC
1/10/10 → 30/11/17
Project: Research

David Wyllie
- School of Neurological and Cardiovascular Sciences - Personal Chair of Ion Channel Physiology and Pharmacology
- Centre for Discovery Brain Sciences - Director
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
Person: Academic: Research Active

Cite this

@article{4c501bd386b941a9ad9b03a118b64194,

title = "Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons",

abstract = "Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes in AMPAR composition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl(-) levels, which determines the reversal potential of GABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential, human stem-cell-derived neurons represent a valuable tool for studying these fundamental properties.",

keywords = "GABA, glutamate, neurotransmitter, patch clamp, qRT-PCR, stem cells, PLURIPOTENT STEM-CELLS, RECEPTOR SUBUNIT EXPRESSION, RAT HIPPOCAMPAL-NEURONS, CEREBRAL WHITE-MATTER, DEVELOPMENTAL REGULATION, REGIONAL SUSCEPTIBILITY, HYPOXIC/ISCHEMIC INJURY, CORTEX, FOREBRAIN, BRAIN",

author = "Livesey, \{Matthew R.\} and Bilada Bilican and Jing Qiu and Rzechorzek, \{Nina Marie\} and Ghazal Haghi and Karen Burr and Hardingham, \{Giles E.\} and Siddharthan Chandran and Wyllie, \{David J. A.\}",

note = "This research was funded by The Wellcome Trust (Grant 092742/Z/10/Z to D.J.A.W., S.C. and G.E.H.), the Medical Research Council (Senior Nonclinical Research Fellowship to G.E.H.), a Wellcome Trust Integrated Training Fellowship for Veterinarians (096409/Z/11/Z to N.M.R.), and the Euan MacDonald Centre and the Fidelity Foundation (to S.C.). ",

year = "2014",

month = mar,

day = "12",

doi = "10.1523/JNEUROSCI.5410-13.2014",

language = "English",

volume = "34",

pages = "4070--4075",

journal = "Journal of Neuroscience",

issn = "0270-6474",

publisher = "Society for Neuroscience",

number = "11",

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TY - JOUR

T1 - Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons

AU - Livesey, Matthew R.

AU - Bilican, Bilada

AU - Qiu, Jing

AU - Rzechorzek, Nina Marie

AU - Haghi, Ghazal

AU - Burr, Karen

AU - Hardingham, Giles E.

AU - Chandran, Siddharthan

AU - Wyllie, David J. A.

N1 - This research was funded by The Wellcome Trust (Grant 092742/Z/10/Z to D.J.A.W., S.C. and G.E.H.), the Medical Research Council (Senior Nonclinical Research Fellowship to G.E.H.), a Wellcome Trust Integrated Training Fellowship for Veterinarians (096409/Z/11/Z to N.M.R.), and the Euan MacDonald Centre and the Fidelity Foundation (to S.C.).

PY - 2014/3/12

Y1 - 2014/3/12

N2 - Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes in AMPAR composition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl(-) levels, which determines the reversal potential of GABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential, human stem-cell-derived neurons represent a valuable tool for studying these fundamental properties.

AB - Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes in AMPAR composition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl(-) levels, which determines the reversal potential of GABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential, human stem-cell-derived neurons represent a valuable tool for studying these fundamental properties.

KW - GABA

KW - glutamate

KW - neurotransmitter

KW - patch clamp

KW - qRT-PCR

KW - stem cells

KW - PLURIPOTENT STEM-CELLS

KW - RECEPTOR SUBUNIT EXPRESSION

KW - RAT HIPPOCAMPAL-NEURONS

KW - CEREBRAL WHITE-MATTER

KW - DEVELOPMENTAL REGULATION

KW - REGIONAL SUSCEPTIBILITY

KW - HYPOXIC/ISCHEMIC INJURY

KW - CORTEX

KW - FOREBRAIN

KW - BRAIN

U2 - 10.1523/JNEUROSCI.5410-13.2014

DO - 10.1523/JNEUROSCI.5410-13.2014

M3 - Article

C2 - 24623784

SN - 0270-6474

VL - 34

SP - 4070

EP - 4075

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 11

ER -

Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

F/SHIP: MISS NINA M RZECHORZEK - USING STEM CELLS TO STUDY NEURONAL-GLIAL INTERACTION IN NEURODEGENERATIVE DISEASE MODELS: THE GLIAL ENVIRONMENT AND NON-CELL-AUTONOMOUS MECHANISMS OF NEURODEGENERATION

Receptors, Function and plasticity in human embryonic stem cell-derived neurons.

FELLOWSHIP: Control of neuroprotection through NMDA receptor dependant regulation of antioxidant status.

Profiles

David Wyllie

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