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Bipolar disorder is a mental illness that includes depressive and manic episodes. It affects about two per cent of people around the globe. The first line of treatment for bipolar disorder is a drug called lithium. Unfortunately, about 70 per cent of bipolar disorder patients don’t respond to it.

A new study published in the Journal of Molecular Psychiatry looked at what causes lithium resistance in neurons generated from induced pluripotent stem cells (iPSCs) derived from bipolar disorder patients that do not respond to lithium clinically (NR). In other words, researchers looked at whether genes had a role to play in lithium response in bipolar disorder patients.

“Lithium has been used for 70 years to treat bipolar disorder and it is still the best treatment to prevent manic episodes and suicide, although only one third of the patients will respond with complete disappearance of the symptoms,” study author Renata Santos told us. “Understanding how lithium works but also why it does not work contributes to the knowledge of the condition and to find new drug targets.”

Researchers wanted to find new genes, mostly outside of the known pathways implicated in bipolar disorder.

“However, it made sense to find so many genes misregulated in the Wnt signaling pathway in the neurons derived from NR patients that are not lithium targets,” study author Carol Marchetto told us. “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.”

Previous studies in the lab had shown that neurons generated from patient iPSCs were more excitable than those derived from healthy individuals’ iPSCs. More interesting, activity of bipolar neurons was reduced by lithium, but only in those generated from patients that responded to lithium.

“This is important,” Santos told us. “It means that we have a cellular model that parallels clinical history of patients and can be used to search for the molecular mechanisms implicated in lithium resistance.”

Researchers had a cohort of iPSC cells derived from patients that responded or not to lithium and also from healthy individuals with similar ages. They generated neurons and looked at the expression of genes in the three groups to search for differences specific to NR neurons using RNA sequencing. LEF1 was one of the repressed top genes and downstream of lithium known targets. The next step was to confirm that LEF1 reduction was driving hyperexcitability.

“Indeed, when this gene was downregulated in healthy neurons excitability increased demonstrating a causal effect,” Marchetto told us. “Also, valproic acid, which is also used to treat bipolar patients, increased LEF1 and Wnt signaling and decreased neuronal activity.”

Researchers found that LEF1, a terminal gene from the Wnt signaling pathway, is repressed in neurons generated from iPSCs from 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 didn’t expect to find unknown targets in the Wnt signaling pathway, which is a major hub of cellular lithium action,” Marchetto told us. “LEF1 is promising as a new target for drug discovery.”