Bipolar disorder, a mood disorder that affects 200 million people around the world, presents something of a mystery to scientists trying to understand the disease on a cellular or genetic level. Bipolar disorder comes in a few varieties, producing manic highs alternating with steep depressions, often alternating in rapid succession. Although the disorder has been shown to run in families, it is not a simple genetic condition caused by a single gene. In a new study published in March in Translational Psychiatry by researchers at the Medical School of the University of Michigan, have undertaken the study of bipolar disorder in stem cells.
The researchers were able to take small skin samples from bipolar persons, and turn them into what are called “induced pluripotent stem cells” or iPSCs. These cells are called “pluripotent” because they may potentially be turned into any of a number of different cells. By careful chemical manipulation, these cells can be encouraged to turn into neurons. By this means, the researchers were able to create the very first stem cell lines specifically derived from people with Bipolar Disorder. Using microarrays (also known as “gene chips”) they were able to look at the expression pattern of tens of thousands of genes to see how the induced neuronal cells from bipolar persons compared with cells from people without the disorder that had been treated the same way.
In comparing the stem cells from bipolar persons with stem cells derived from those who were not bipolar, the researchers saw specific differences in the behavior of and communication between the neurons. More specifically, the researchers were looking at how the neurons differed in their patterns of gene expression; at the process by which they differentiate (develop) into neurons; and how they communicate. They also found significant differences in the neurons’ responses to lithium (a psycho-pharmaceutical commonly prescribed for bipolar disorder), according to Sue O’Shea, Ph.D., a University of Michigan stem cell specialist who helped lead the work.
Analysis of the bipolar neurons showed that these cells expressed more ion channels and membrane receptors than non-bipolar cells; and in particular, the bipolar cells showed more channels and receptors that specifically use calcium to send and receive signals. Calcium is very important in neuronal development and function. Differences in calcium signaling in early development may have an impact in later years that manifest as bipolar disorder – or perhaps other mental health conditions.
The implications of this research are rather substantial. Melvin McInnis, M.D., one of the principal investigators explains that they can now test potential psychopharmaceuticals to see what effect they have in these cultured cells rather than using a trial-and-error approach. Also, although lithium is the treatment of choice for bipolar disorder, it can have side effects; the new cell lines will make it possible to study how lithium alters calcium signals in vitro (in a petri dish), and specifically in cells derived from bipolar persons. This is good news for persons affected by bipolar disorder, and their families, who may experience frustration with the current limited treatment options. The research also offers the possibility of treating bipolar disorder with what’s called “personalized medicine,” whereby treatment options are tailored to the individual patient’s symptoms and genetic profile.
Future directions for this research team include the development of stem cell lines derived from other trial participants with bipolar disorder; this can take months as they generate mature neurons for study. Also upcoming for the team is the development of rapid tests (assays) to screen the effect of potential drug candidates on the cultured neurons.
By Laura Prendergast