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

Molecular Psychiatry volume 26, pages 2440–2456 (2021)Cite this article

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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.

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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.

Author information

Author notes

  1. These authors contributed equally: Renata Santos, Sara B. Linker, Shani Stern

  2. These authors jointly supervised this work: Maria C. Marchetto, Fred H. Gage

Authors and Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Renata Santos, Sara B. Linker, Shani Stern, Ana P. D. Mendes, Lynne Randolph-Moore, Vipula Racha, Yeni Kim, Maria C. Marchetto & Fred H. Gage

  2. University of Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, 102 Rue de la Santé, 75014, Paris, France

    Renata Santos

  3. Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, 3498838, Israel

    Shani Stern

  4. The Razavi Newman Integrative Genomics and Bioinformatics Core (IGC), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Maxim N. Shokhirev & Galina Erikson

  5. Department of Psychiatry, Dongguk University International Hospital, 27 Donggukro Ilsandonggu, 10326, Goyang, South Korea

    Yeni Kim

  6. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    John R. Kelsoe

  7. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Anne G. Bang

  8. Department of Psychiatry, Dalhousie University, 5909 Veterans’ Memorial Lane, Halifax, NS, B3H 2E2, Canada

    M. Alda

  9. Department of Anthropology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Maria C. Marchetto

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  1. Renata Santos
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  2. Sara B. Linker
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  3. Shani Stern
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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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