After searching for decades, researchers have discovered important clues about how lithium, a mainstay of treatment for many people with bipolar disorder, alters the function of neurons to prevent manic episodes. The findings, reported June 16 in the journal eLife, point scientists toward specific biological pathways involved in the drug’s activity and suggest strategies for developing new treatments for bipolar disorder.

Lithium has been used as a mood stabilizer for more than 60 years, but scientists still know very little about how it works. In the new study, Lisa Monteggia, Ph.D., of the University of Texas Southwestern Medical Center and colleagues explored the drug’s impact on a protein called brain-derived neurotrophic factor (BDNF), which supports the growth of neurons in the brain.

Dr. Monteggia has twice received Foundation Young Investigator Grants and in 2010 was an Independent Investigator Grantee. She also received a Distinguished Investigator Award in 2014 and was the recipient of the Daniel X. Freedman Award in 2005. Also involved in the research was Dr. Ege Kavalali, who was awarded a Foundation Distinguished Investigator in 2013.

BDNF is a protein that influences the degree to which neurons in the brain form connections with one another. People with bipolar disorder often have low levels of BDNF, and lithium treatment boosts these levels. It has not been known, however, whether this is how the drug stabilizes patients’ moods.

Through a series of experiments in mice and in cultured neurons, Dr. Monteggia and her colleagues determined that BDNF is involved in lithium’s anti-manic effects (it is not involved in the drug’s anti-depressive properties). The team’s research pinpointed the involvement of BDNF and its receptor, called TrkB, in a signal whose impact is to reduce the presence of certain neurotransmitter receptors (so-called AMPA receptors) on neurons’ outer surfaces, thereby altering the way those cells communicate with other neurons. By identifying the involvement of specific genes and pathways in lithium’s anti-manic effects, the findings could help guide the development of better therapies.

Although lithium reduces the symptoms of both mania and depression in people with bipolar disorder, the study did not uncover a cause for lithium’s antidepressant effects. In fact, the team found that lithium reduces depression-like behavior in mice even when they lack the gene for BDNF. This result opens avenues towards the discovery of novel antidepressants.