New stem cell research on bipolar disorder, conducted by the University of Michigan Medical School and the Heinz C. Prechter Bipolar Research Fund, is helping to uncover the molecular mechanisms underlying this disabling psychiatric illness. In a study reported in the March 25, 2014 issue of Translational Psychiatry, a team of researchers led by K. Sue O’Shea and Melvin McInnis created the first stem cell lines generated from patients with bipolar disorder. When the team then prompted the stem cells to become neurons, they uncovered several differences between the brain cells of patients and healthy controls that point to abnormalities in brain development and calcium signaling.
“This is an important and exciting study,” said Chris Ross, director of the Molecular Neurobiology Laboratory of Johns Hopkins University in Baltimore, Maryland, who was not involved in the study. The current study is a jumping off point for further studies with these cells “that will help us better understand the disease, and more importantly, develop new treatments,” he said.
The 5.7 million Americans with bipolar disorder suffer from alternating cycles of severe mood highs and lows that affect all aspects of their social and occupational functioning. Current treatment options for the illness are limited, and the development of better drugs requires a deeper understanding of underlying brain mechanisms. Progress on this front is slowed by an inherent challenge of studying brain disorders – detailed analyses of brain tissue can only be conducted on postmortem tissue that is very difficult to obtain.
Feeding neurospheres formed from induced pluripotent stem cells obtained from a patient with bipolar disorder.
The potential of stem cells
Recent advances, however, have enabled scientists to coax adult skin cells obtained during a simple biopsy back into an immature and pluripotent state, meaning that with the right guidance these stem cells can be developed into any cell type in the body, including neurons. These induced pluripotent stem (iPS) cells have opened up a new avenue for studying complex neurological disorders in living patients, enabling scientists to compare the neurons of people with a disease to those from healthy individuals without relying on brain tissue.
Although converting iPS cells into neurons has proved more difficult than originally envisioned, the cells are now being used to study a wide range of brain disorders including Alzheimer’s and Huntington’s disease. So far, iPS cells have been able to reproduce many of the known neuronal defects in these well-characterized illnesses, demonstrating their value as a disease model and suggesting that for more enigmatic diseases like bipolar disorder the cells will “provide novel insight and important ways to approach problems that could never have been approached before,” said Ross.
Calcium complications
O’Shea, McInnis, and colleagues collected skin samples from patients with bipolar disorder and healthy controls. By carefully controlling the cells’ environment, the researchers regressed the mature cells back into a state of immaturity, then prompted these stem cells to become mature neurons. A comparison of the neurons from people with bipolar disorder to those from healthy individuals revealed several key differences.
Neurons derived from bipolar disorder iPS cells expressed more membrane receptors and ion channels related to calcium signaling – a key aspect of neuronal development and communication – than those in control neurons. The current findings are in agreement prior studies using other methods that have pointed to abnormal calcium signaling in bipolar disorder. Genetic findings have linked a mutation in a particular calcium channel gene to the illness, and lithium, the major drug used to even out the highs and lows, also affects calcium signaling. In the current study, the neurons derived from patients with bipolar disorder also differed from controls in the way that they responded to lithium treatment.
“Signals between nerve cells are fundamental to brain functioning,” McInnis points out and “a model for brain functioning opens the door for developing and testing novel treatments.”
Dr. Monica Bame passaging induced pluripotent stem cells generated from a patient with bipolar disorder.
Divergent Development
Although the symptoms of bipolar disorder typically emerge in late adolescence or early adulthood, the underlying brain abnormalities seem to be present much earlier. In the current study, O’Shea, McInnis, and colleagues report new evidence of such developmental defects. During early embryonic development, neurons are born specific brain areas and then migrate to their proper location. The bipolar iPS-derived neurons differed in their expression of factors that control where in the brain these neurons end up, suggesting that some neurons may not reach their correct destination in the illness.
The results of the new study have implications beyond bipolar disorder and other mood disorders. “This is a very promising demonstration of the potential value of cellular models of brain diseases,” said Roy Perlis, medical director of the Bipolar Clinic and Research Program of Massachusetts General Hospital in Boston (who was not affiliated with the study). “It's a technology that may change how we study these diseases, and while we have a lot still to learn, this paper provides a glimmer of what may be ahead.”
What lies directly ahead is an expansion of the current preliminary study. O’Shea, McInnis, and colleagues are in the process of developing additional cell lines from new patients to expand their research, and will make all lines available to the wider neuropsychiatric research community.