Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks
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. I...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-01270-x |
| _version_ | 1798034870922903552 |
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| author | Ana Gonzalez-Ramos Eliška Waloschková Apostolos Mikroulis Zaal Kokaia Johan Bengzon Marco Ledri My Andersson Merab Kokaia |
| author_facet | Ana Gonzalez-Ramos Eliška Waloschková Apostolos Mikroulis Zaal Kokaia Johan Bengzon Marco Ledri My Andersson Merab Kokaia |
| author_sort | Ana Gonzalez-Ramos |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-04-11T20:49:17Z |
| format | Article |
| id | doaj.art-a2e6959621cd4950a88ad99f5f68143b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T20:49:17Z |
| publishDate | 2021-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a2e6959621cd4950a88ad99f5f68143b2022-12-22T04:03:53ZengNature PortfolioScientific Reports2045-23222021-11-0111111610.1038/s41598-021-01270-xHuman stem cell-derived GABAergic neurons functionally integrate into human neuronal networksAna Gonzalez-Ramos0Eliška Waloschková1Apostolos Mikroulis2Zaal Kokaia3Johan Bengzon4Marco Ledri5My Andersson6Merab Kokaia7Epilepsy Center, Department of Clinical Sciences, Lund University HospitalEpilepsy Center, Department of Clinical Sciences, Lund University HospitalEpilepsy Center, Department of Clinical Sciences, Lund University HospitalLund Stem Cell Center, Department of Clinical Sciences, Lund University HospitalDepartment of Clinical Sciences, Lund UniversityEpilepsy Center, Department of Clinical Sciences, Lund University HospitalEpilepsy Center, Department of Clinical Sciences, Lund University HospitalEpilepsy Center, Department of Clinical Sciences, Lund University HospitalAbstract 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.https://doi.org/10.1038/s41598-021-01270-x |
| spellingShingle | Ana Gonzalez-Ramos Eliška Waloschková Apostolos Mikroulis Zaal Kokaia Johan Bengzon Marco Ledri My Andersson Merab Kokaia Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks Scientific Reports |
| title | Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks |
| title_full | Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks |
| title_fullStr | Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks |
| title_full_unstemmed | Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks |
| title_short | Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks |
| title_sort | human stem cell derived gabaergic neurons functionally integrate into human neuronal networks |
| url | https://doi.org/10.1038/s41598-021-01270-x |
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