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Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

Authors :
Yeni Kim
John R. Kelsoe
Maria C. Marchetto
Ana P.D. Mendes
Maxim N. Shokhirev
Galina Erikson
Martin Alda
Lynne Randolph-Moore
Sara B. Linker
Fred H. Gage
Renata Santos
Anne G. Bang
Shani Stern
Vipula Racha
The Salk Institute for Biological Studies
Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
University of Haifa [Haifa]
Dongguk University (DU)
Department of Psychiatry [San Diego, CA, États-Unis]
University of California [San Diego] (UC San Diego)
University of California-University of California
Sanford Burnham Prebys Medical Discovery Institute
Dalhousie University [Halifax]
University of California
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
University of California (UC)-University of California (UC)
University of California (UC)
Martinez Rico, Clara
Source :
Molecular Psychiatry, Molecular Psychiatry, Nature Publishing Group, 2021, Online ahead of print. ⟨10.1038/s41380-020-00981-3⟩, Molecular Psychiatry, 2021, Online ahead of print. ⟨10.1038/s41380-020-00981-3⟩
Publication Year :
2021
Publisher :
HAL CCSD, 2021.

Abstract

International audience; 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/βcatenin 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. Additionally, 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.

Details

Language :
English
ISSN :
13594184 and 14765578
Database :
OpenAIRE
Journal :
Molecular Psychiatry, Molecular Psychiatry, Nature Publishing Group, 2021, Online ahead of print. ⟨10.1038/s41380-020-00981-3⟩, Molecular Psychiatry, 2021, Online ahead of print. ⟨10.1038/s41380-020-00981-3⟩
Accession number :
edsair.doi.dedup.....4ba7b83c172317af60605a29e5bdefeb