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

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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Fig. 1: NR neurons became transcriptionally distinct during differentiation.
Fig. 2: Dysregulation of Wnt/β-catenin signaling in NR neurons.
Fig. 3: Downregulation of LEF1 gene and Wnt/β-catenin signaling impairment in NR neurons.
Fig. 4: VPA increases Wnt/β-catenin signaling and induces LEF1 expression.
Fig. 5: Hyperexcitability is modulated by VPA and LEF1 expression.
Fig. 6: Model of action of Li and VPA on LEF1 expression and hyperexcitability in NR neurons.

Data availability

GEO Accession number is GSE159487.

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Acknowledgements

We thank the Salk Institute Core Facilities: Next Generation Sequencing (NGS) Core Facility with funding from NIH-NCI CCSG: P30 014195, the Chapman Foundation and the Helmsley Charitable Trust; The Razavi Newman Integrative Genomics and Bioinformatics Core Facility with funding from NIH-NCI CCSG: P30 014195; and Flow Cytometry Core Facility with funding from NIH-NCI CCSG: P30 014195. We would also like to thank M.L. Gage for editorial comments. This work was supported by the National Cancer Institute (Grant No. P30 CA014195) and the National Institutes of Health (Grant No. R01AG05651) and by the National Cooperative Reprogrammed Cell Research Groups (NCRCRG; Grant No. U19 MH106434). The Gage laboratory is supported in part by the JPB Foundation, Annette C. Merle-Smith, and the Robert and Mary Jane Engman Foundation. SS acknowledges Zuckerman STEM leadership program funding.

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Correspondence to Renata Santos, Maria C. Marchetto or Fred H. Gage.

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Santos, R., Linker, S.B., Stern, S. et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry 26, 2440–2456 (2021). https://doi.org/10.1038/s41380-020-00981-3

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