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Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids

Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects o...

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Autores principales: Osete, Jordi Requena, Akkouh, Ibrahim A., Ievglevskyi, Oleksandr, Vandenberghe, Matthieu, de Assis, Denis Reis, Ueland, Thor, Kondratskaya, Elena, Holen, Børge, Szabo, Attila, Hughes, Timothy, Smeland, Olav B., Steen, Vidar Martin, Andreassen, Ole A., Djurovic, Srdjan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615757/
https://www.ncbi.nlm.nih.gov/pubmed/36653674
http://dx.doi.org/10.1038/s41380-023-01944-0
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author Osete, Jordi Requena
Akkouh, Ibrahim A.
Ievglevskyi, Oleksandr
Vandenberghe, Matthieu
de Assis, Denis Reis
Ueland, Thor
Kondratskaya, Elena
Holen, Børge
Szabo, Attila
Hughes, Timothy
Smeland, Olav B.
Steen, Vidar Martin
Andreassen, Ole A.
Djurovic, Srdjan
author_facet Osete, Jordi Requena
Akkouh, Ibrahim A.
Ievglevskyi, Oleksandr
Vandenberghe, Matthieu
de Assis, Denis Reis
Ueland, Thor
Kondratskaya, Elena
Holen, Børge
Szabo, Attila
Hughes, Timothy
Smeland, Olav B.
Steen, Vidar Martin
Andreassen, Ole A.
Djurovic, Srdjan
author_sort Osete, Jordi Requena
collection PubMed
description Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.
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spelling pubmed-106157572023-11-01 Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids Osete, Jordi Requena Akkouh, Ibrahim A. Ievglevskyi, Oleksandr Vandenberghe, Matthieu de Assis, Denis Reis Ueland, Thor Kondratskaya, Elena Holen, Børge Szabo, Attila Hughes, Timothy Smeland, Olav B. Steen, Vidar Martin Andreassen, Ole A. Djurovic, Srdjan Mol Psychiatry Article Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry. Nature Publishing Group UK 2023-01-18 2023 /pmc/articles/PMC10615757/ /pubmed/36653674 http://dx.doi.org/10.1038/s41380-023-01944-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Osete, Jordi Requena
Akkouh, Ibrahim A.
Ievglevskyi, Oleksandr
Vandenberghe, Matthieu
de Assis, Denis Reis
Ueland, Thor
Kondratskaya, Elena
Holen, Børge
Szabo, Attila
Hughes, Timothy
Smeland, Olav B.
Steen, Vidar Martin
Andreassen, Ole A.
Djurovic, Srdjan
Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title_full Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title_fullStr Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title_full_unstemmed Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title_short Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
title_sort transcriptional and functional effects of lithium in bipolar disorder ipsc-derived cortical spheroids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615757/
https://www.ncbi.nlm.nih.gov/pubmed/36653674
http://dx.doi.org/10.1038/s41380-023-01944-0
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