Downregulation of the LEF1 gene may be responsible for lithium resistance in people with bipolar disorder who do not respond to lithium according to a study published in Nature.

The researchers studied patients with type I bipolar disorder who participated in genetic studies at Dalhousie University in Nova Scotia, Canada. All participants in the current study were white males in their 40s. The researchers extracted cells and performed RNA sequencing analysis.

Analysis showed that Li-non-responsive (NR) neurons are distinct from control and Li-responsive (LR) neurons. These differences increase throughout differentiation.

Research also showed gene clustering of LR and NR samples distinctly from controls, which suggests that these gene sets “represented pathways that were disrupted in both LR and NR bipolar patient-derived neurons,” the researchers said. Researchers also found “extensive dysregulation of Wnt/β-catenin signaling in NR neurons.”


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Furthermore, LEF1 was downregulated and Wnt/β-catenin signaling is impaired in NR neurons. The researchers concluded, “iPSC-derived neurons from NR and LR bipolar patients exhibit markedly different molecular changes that are associated with hyperexcitability, and that modulation of LEF1 may be key in ameliorating disease pathology in NR patients.”

Limitations of this study were the small sample size, which was made up solely of men.

We also spoke with two of the study authors, Renata Santos, PhD, senior staff researcher at the Institute of Psychiatry and Neuroscience of Paris and Carol Marchetto, PhD, senior staff scientist at the Salk Institute for Biological Studies.

1. What are the highlights of your study?

Lithium is a hallmark in bipolar disorder (BD) treatment and research. It has been used for 70 years and it is still the best treatment to prevent manic episodes and the only one that prevents suicide, although only one third of the patients will respond with complete disappearance of symptoms. Understanding how lithium works and also why it does not work contributes to the knowledge of the condition and to find new drug targets. We were interested in what causes lithium resistance in neurons generated from induced pluripotent stem cells (iPSC) derived from patients that do not respond to lithium (NR) clinically. Our aim was to find targets for development of new treatments for BD and we did find LEF1 which is promising as a new target for drug discovery.

2.  Why is this study important now?

BD is a devastating disorder that impacts daily life and social integration of the patients that affects 2% of the world population. Lithium has been used for 70 years and second-generation antipsychotics for 20 years as first-line treatments for mood stabilization with up to 20-30% of the patients that not responding. Therefore, patients are frequently treated with complex polypharmacy, leading to high medication burden and high health care costs. Therefore, developing new treatments for BD that are more effective, tolerable and safe (especially for children and pregnant women) is urgently needed.

3.  What did you find when you searched for specific targets related to Li resistance? What surprised you about the results?

We found that LEF1, a terminal gene from the Wnt signaling pathway, is repressed in neurons generated from iPSCs in bipolar disorder patients that do not respond to lithium treatment. Reduction in LEF1 was responsible for increased neuronal activity and lithium resistance in cultured neurons. We wanted to find new genes, mostly outside of the known pathways, implicated in bipolar disorder. We were surprised to find so many genes misregulated in the Wnt signaling pathway in the neurons derived from NR patients because this pathway is a major hub of cellular lithium action.

4. In your study, you wrote: One hypothesis to explain hyperexcitability is the dysregulation of Wnt signaling. Why or how is the dysregulation of Wnt signaling important with regards to Bipolar Disorder?

Actually, lithium and other drugs used to treat the patients change the regulation of the Wnt pathway. This is a fundamental cellular signaling pathway; it is implicated in embryonic brain development and cancer, for example.

5. What further research is needed?

Research is still need to evaluate the potential of LEF1 as a target for drug discovery and to find new potential treatments.

Reference

Santos R, Linker SB, Stern S, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry. Published online January 4, 2021. doi:10.1038/s41380-020-00981-3