Inherited Depression Linked To Shortage Of Cells In Brain Region

"One of the things we hope may result from our findings is the recognition that there are important differences between patients with a familial history of depression and those without," says Joseph L. Price, Ph.D., who headed the research. "There might also be differences in appropriate drug therapies."

Price is a professor of anatomy and neurobiology at Washington University School of Medicine in St. Louis. His graduate student Dost Öngür is lead author of a paper in the Oct. 27 issue of Proceedings of the National Academy of Sciences.

The second author, Wayne C. Drevets, M.D., reported in 1997 that positron emission tomography images of people with familial depression showed less activity in a thumbnail-sized area of the brain behind the mid-forehead. This region, the subgenual prefrontal cortex, also was smaller than in healthy people, magnetic resonance images revealed.

"Dost and I wanted to identify the cellular basis for this difference in size," Price explains.

Using samples from the Harvard Brain Tissue Resource Center, Öngür compared the number of cells in the subgenual prefrontal cortex of mentally healthy people with that of people who had suffered from unipolar depression or bipolar disorder, which involves highs as well as lows.

He used a technique called stereology, which samples several parts of a specimen to accurately estimate the total number of cells. "It's the same idea as when you conduct an opinion poll by talking to a few thousand representative people," he says. "In the case of cells, it minimizes the danger of double counting and other problems people have had in the past."

The researchers were expecting to see a discrepancy in the number of neurons. But to their surprise, there was instead a big difference in the number of cells called glia. These housekeeping cells recycle ions and chemicals that come out of neurons. They also respond to the stress hormone cortisol and to serotonin, which is depleted in depression.

Using a larger number of tissue samples from the Stanley Foundation in Bethesda, Md., Öngür and Price were able to confirm this result and show that the decreased number of glia is restricted to patients with a family history of depression.

Without knowing Öngür's results, Drevets had read the medical reports of the donors, deciding which cases were familial and which were not. People classified with familial depression had a first degree relative, a parent, sibling or child, who also had been depressed. Drevets, a psychiatrist, is at the University of Pittsburgh School of Medicine. He conducted his original study at Washington University School of Medicine.

"It turned out that only the samples from people with familial depression had a decreased number of glia," Price says. "That suggests that this deficit may relate to the genetic difference that gives people a tendency to become depressed."

The difference in familial cases amounted to between 25 percent and 40 percent. The subgenual prefrontal cortex of the controls contained about 9 million glia. The number was reduced to about 7 million in the people with familial unipolar depression and to about 5.4 million in the people with familial bipolar disorder.

Medication effects were unlikely to account for the difference, Price explains, because both the familial and the other depressed patients had taken medications. And the unipolar and bipolar patients had taken different types of drugs, yet both had fewer glial cells. Depression itself was unlikely to be the culprit because the patients with nonfamilial depression did not have fewer glia.

A shortage of glia in the subgenual prefrontal cortex is particularly interesting, Price says. His studies have revealed that this area is one of the few regions of the cortex that connect to the hypothalamus and other structures involved in stress responses. The periaqueductal gray responds to pain and sickness, for example. "It makes you become very quiet and retreat to a safe place," Price says. "That response is remarkably similar to depression, where people show social withdrawal and lack of activity."

The researchers now want to determine which type of glia is in short supply and what the consequences could be. "By studying the causes and results of these changes, we might be able to explain in the future how depression and mania arise as a consequence of changes in brain activity," Öngür says.

Öngür D, Drevets WC, Price JL (1998). Glial reduction in the subgenual prefrontal cortex in mood disorders. Proceedings of the National Academy of Sciences, 95, 13290-13295.

Grants from the U.S. Public Health Service, the National Institutes of Health and the Charles A. Dana Foundation supported this research.