Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
24
08
2022
accepted:
06
01
2023
revised:
29
12
2022
medline:
1
11
2023
pubmed:
19
1
2023
entrez:
18
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36653674
doi: 10.1038/s41380-023-01944-0
pii: 10.1038/s41380-023-01944-0
pmc: PMC10615757
doi:
Substances chimiques
Lithium
9FN79X2M3F
Lithium Compounds
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3033-3043Subventions
Organisme : Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)
ID : 2022087
Organisme : Norges Forskningsråd (Research Council of Norway)
ID : 300309
Organisme : Norges Forskningsråd (Research Council of Norway)
ID : 223273
Organisme : Norges Forskningsråd (Research Council of Norway)
ID : 248828
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 80113
Informations de copyright
© 2023. The Author(s).
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