Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders

Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA tr...

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Bibliographic Details
Published in:Molecular psychiatry 2021-11, Vol.26 (11), p.6789-6805
Main Authors: Osete, Jordi Requena, Akkouh, Ibrahim A., de Assis, Denis Reis, Szabo, Attila, Frei, Evgeniia, Hughes, Timothy, Smeland, Olav B., Steen, Nils Eiel, Andreassen, Ole A., Djurovic, Srdjan
Format: Article
Language:English
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Antimanic Agents - pharmacology
Antimanic Agents - therapeutic use
Behavioral Sciences
Biological Psychology
Bipolar disorder
Electron transport
Glycolysis
Growth
Health aspects
Humans
Induced Pluripotent Stem Cells
Lamotrigine
Lithium
Lithium - pharmacology
Medicine
Medicine & Public Health
Mitochondria
Molecular modelling
Neural Stem Cells
Neurosciences
Oxidative phosphorylation
Oxygen consumption
Patients
Pharmacotherapy
Phosphorylation
Pluripotency
Psychiatry
Respiration
Stem cells
Thermogenesis
Transcription
Valproic acid
Valproic Acid - pharmacology
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Summary:Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-021-01164-4