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Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks

Gonzalez-Ramos, Ana LU ; Waloschková, Eliška ; Mikroulis, Apostolos LU ; Kokaia, Zaal LU orcid ; Bengzon, Johan LU ; Ledri, Marco LU ; Andersson, My LU orcid and Kokaia, Merab LU (2021) In Scientific Reports 11(1).
Abstract

Gamma-aminobutyric acid (GABA)-releasing interneurons modulate neuronal network activity in the brain by inhibiting other neurons. The alteration or absence of these cells disrupts the balance between excitatory and inhibitory processes, leading to neurological disorders such as epilepsy. In this regard, cell-based therapy may be an alternative therapeutic approach. We generated light-sensitive human embryonic stem cell (hESC)-derived GABAergic interneurons (hdIN) and tested their functionality. After 35 days in vitro (DIV), hdINs showed electrophysiological properties and spontaneous synaptic currents comparable to mature neurons. In co-culture with human cortical neurons and after transplantation (AT) into human brain tissue resected... (More)

Gamma-aminobutyric acid (GABA)-releasing interneurons modulate neuronal network activity in the brain by inhibiting other neurons. The alteration or absence of these cells disrupts the balance between excitatory and inhibitory processes, leading to neurological disorders such as epilepsy. In this regard, cell-based therapy may be an alternative therapeutic approach. We generated light-sensitive human embryonic stem cell (hESC)-derived GABAergic interneurons (hdIN) and tested their functionality. After 35 days in vitro (DIV), hdINs showed electrophysiological properties and spontaneous synaptic currents comparable to mature neurons. In co-culture with human cortical neurons and after transplantation (AT) into human brain tissue resected from patients with drug-resistant epilepsy, light-activated channelrhodopsin-2 (ChR2) expressing hdINs induced postsynaptic currents in human neurons, strongly suggesting functional efferent synapse formation. These results provide a proof-of-concept that hESC-derived neurons can integrate and modulate the activity of a human host neuronal network. Therefore, this study supports the possibility of precise temporal control of network excitability by transplantation of light-sensitive interneurons.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
22050
publisher
Nature Publishing Group
external identifiers
  • scopus:85118952314
  • pmid:34764308
ISSN
2045-2322
DOI
10.1038/s41598-021-01270-x
language
English
LU publication?
yes
id
76095d8d-c54f-440b-8817-1fae680b8741
date added to LUP
2022-01-14 12:48:35
date last changed
2022-01-15 03:00:04
@article{76095d8d-c54f-440b-8817-1fae680b8741,
  abstract     = {<p>Gamma-aminobutyric acid (GABA)-releasing interneurons modulate neuronal network activity in the brain by inhibiting other neurons. The alteration or absence of these cells disrupts the balance between excitatory and inhibitory processes, leading to neurological disorders such as epilepsy. In this regard, cell-based therapy may be an alternative therapeutic approach. We generated light-sensitive human embryonic stem cell (hESC)-derived GABAergic interneurons (hdIN) and tested their functionality. After 35 days in vitro (DIV), hdINs showed electrophysiological properties and spontaneous synaptic currents comparable to mature neurons. In co-culture with human cortical neurons and after transplantation (AT) into human brain tissue resected from patients with drug-resistant epilepsy, light-activated channelrhodopsin-2 (ChR2) expressing hdINs induced postsynaptic currents in human neurons, strongly suggesting functional efferent synapse formation. These results provide a proof-of-concept that hESC-derived neurons can integrate and modulate the activity of a human host neuronal network. Therefore, this study supports the possibility of precise temporal control of network excitability by transplantation of light-sensitive interneurons.</p>},
  author       = {Gonzalez-Ramos, Ana and Waloschková, Eliška and Mikroulis, Apostolos and Kokaia, Zaal and Bengzon, Johan and Ledri, Marco and Andersson, My and Kokaia, Merab},
  issn         = {2045-2322},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks},
  url          = {http://dx.doi.org/10.1038/s41598-021-01270-x},
  doi          = {10.1038/s41598-021-01270-x},
  volume       = {11},
  year         = {2021},
}