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Research Focus: Bipolar Disorder in a Dish

A research study has used a new cellular model to see “inside” the brains of people with bipolar disorder.

We can’t always see what we want to see inside the bodies of living people, despite all the technology we have for looking—from X-ray to MRI to endoscopy.  In particular, our methods for looking at living people’s brains are pretty limited. One of the common ways around this, especially when we want to learn about a disorder affecting humans is to study a model of the illness.

Animal models are the most common—say, a mouse or rat that has been subjected to stress or trauma and shows signs of anxiety or depression. Such models are somewhat limited since we can’t ask the animal how it is feeling, and because rodent behavior is much less complicated than human behavior.

A cellular model is another option—a cell that can be grown in the lab and studied in different ways under different circumstances. In this case, if the cell is derived from a person with an illness, it will have the genetic make-up that characterizes that disorder. Again, the model is limited, but it allows researchers to see cellular behavior that can’t be observed inside a living person.

Creating Neurons

Neurons of people with bipolar disorder.

Neurons created from skin cells can be seen here in white and red. Image courtesy of Salk Institute.

A recent study published in Nature shows differences between brain cells of people with bipolar disorder and people without, providing a cellular model for studying how bipolar disorder works in the brain.

This study used a fairly new method called induced pluripotent stem cell (iPSC) technology to reprogram skin cells into neurons, the electrically active cells that carry information around the brain.

Skin cells were taken from 6 people with bipolar disorder, 3 who responded to lithium treatment and 3 who did not. The researchers created neurons similar to those from the hippocampus area of the brain, which appears to be different in people with bipolar disorder.

The study showed that the neurons of the people with bipolar disorder were distinctly more excitable than those from people without the disorder, showing more electrical activity both spontaneously and when stimulated. In addition, the mitochondria of the “bipolar cells” were more active. Mitochondria are specialized compartments inside all our cells, creating energy for the cells to operate.

“Researchers hadn’t all agreed that there was a cellular cause to bipolar disorder,” said the study’s senior author, Rusty Gage, of the Salk Institute’s Laboratory of Genetics. “So our study is important validation that the cells of these patients really are different.”

Even more interesting was that when the bipolar neurons were given a lithium “bath,” the neurons of the lithium responders calmed down to appear more like the neurons from people without bipolar disorder. The neurons from the people who didn’t respond to lithium didn’t calm down with the lithium bath.

What’s the Point?

This new cellular model of bipolar disorder could be useful for helping us to understand what is happening in the brains of people with bipolar disorder. Ultimately, knowing more about what makes these cells hyperexcitable could help lead to better treatments.

As with all mental illnesses, bipolar disorder can be very difficult to treat. Lithium is the oldest psychotropic medication, having been used as long ago as the 1870s for treating mania, though its modern use dates back to 1949. Like other psychotropic medications, it doesn’t work for everyone, though it works very effectively for some. For those who don’t respond to lithium, it can be hard to treat bipolar disorder, since no other drug targets both bipolar states. Anti-depressants can trigger mania, and treatments for mania don’t help with depression.

It would be very useful to know why some people respond to lithium and others don’t. In a practical sense, this cellular model could lead to simple tests that would predict an individual’s response to medications, making it faster and easier to find the right treatment for each individual.

Though it’s exciting, this was a tiny study, using cells from only 6 people with bipolar disorder. The researchers are continuing this work by studying the cells of more people and under different conditions, which will give a much better sense of how much we can really learn about bipolar disorder from these cells.

More Reading

The research paper: Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

The press release

An article about the study, written for scientists (with a link to a “Plain English” version): Patient-Derived Bipolar Neurons Reproduce Clinical Response to Lithium

A blog that’s a good resource: Bipolar Burble

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