ArticleMolecular psychiatry2021
Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 2 of them syntheses that pooled it.
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Who cites it
34 citing papers in PubMed, 2 syntheses or guidelines pooled it, 75 citations in OpenAlex.
- Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients' neurons.Molecular psychiatry · 2025Pooled it
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- Integrative multi-omics identifiesPsychological medicine · 2026Article
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.American journal of human genetics · 2026Article
- Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B.bioRxiv : the preprint server for biology · 2025Article
- Detecting suicide risk in bipolar disorder patients from lymphoblastoid cell lines genetic signatures.Translational psychiatry · 2025Article
- The Mechanisms of Lithium Action: The Old and New Findings.Pharmaceuticals (Basel, Switzerland) · 2025Review
- The Impact of Electrophysiological Diversity on Pattern Completion in Lithium Nonresponsive Bipolar Disorder: A Computational Modeling Approach.Brain and behavior · 2025Article
- Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.Molecular psychiatry · 2024Article
- Progress and Implications from Genetic Studies of Bipolar Disorder.Neuroscience bulletin · 2024Review
- Valproate-Induced Thrombocytopenia: A Case Report.Cureus · 2024Article
- Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocampal Neurogenesis.Biomolecules · 2024Article
- Single-cell genomics and regulatory networks for 388 human brains.Science (New York, N.Y.) · 2024Article
- Focusing on the tetra-partite synapse in Parkinson's disease research using human patient-derived neurons.Neural regeneration research · 2024Article
- Single-cell genomics and regulatory networks for 388 human brains.bioRxiv : the preprint server for biology · 2024Article
- Stem cell therapy for the treatment of psychiatric disorders: a real hope for the next decades.Frontiers in psychiatry · 2024Review
- Exploring mood disorders and treatment options using human stem cells.Genetics and molecular biology · 2024Article
- Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.Molecular psychiatry · 2024Article
- Pharmacogenomics and response to lithium in bipolar disorder.Pharmacogenomics · 2024Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 5 countries.
Funding
Abstract
Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.
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