Oct. 18, 2004 ANN ARBOR, MI - The brains of people with severe depression have lower levels of several related molecules that are key to the development, organization, growth and repair of the brain than the brains of people without the disease, or those with the bipolar form of depression, a new study finds.
The discovery, which surprised researchers in the multi-university consortium that made it, suggests a whole new direction for understanding depression and developing new depression treatments. It may even help scientists understand how some antidepressant medications work in the brain to ease symptoms, and why there is wide variation in how depressed people respond to different antidepressants.
The finding was made in two specific areas of the brain known to be important to depression. The study relied on microarray analysis of 32 post-mortem brain samples — the microarray method can simultaneously measure the level of activity of tens of thousands of genes that are functional in a given tissue.
The researchers found that levels of molecules called fibroblast growth factors (FGFs), and two of the receptors that bind to them, were significantly lower among people who had been diagnosed with severe clinical depression and had died in a depressed state. There was also some indication that those depressed people who had been taking antidepressants before their deaths had levels of FGF and FGF receptors that were closer to normal.
The results are published online this week in the early edition of the Proceedings of the National Academy of Sciences by researchers from the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Family Philanthropic Fund and by the National Institute of Mental Health. The research team consisted of scientists from the University of Michigan's Mental Health Research Institute and Department of Psychiatry, working in close collaboration with researchers from the University of California's Davis and Irvine campuses and from Stanford University.
“This finding comes from a completely unbiased search that began with no hypothesis, to find what genes best differentiate major depression brains from normal and bipolar brains,” says senior author Huda Akil, Ph.D., the Gardner C. Quarton Distinguished Professor of Neurosciences in Psychiatry at U-M. “A wide set of individual genes came up as different between the depressed and control individuals, but the family of genes that was most different and showed the highest significance as a coherent group was the FGF family. This suggests a more profound change in an entire system of communication and control within the brain.”
No previous studies have directly examined the role of FGFs or their receptors in psychiatric illnesses. Another growth factor, called Brain Derived Neurotrophic Factor, has been hypothesized to play a role in the effects of stress on the brain and in the mode of action of antidepressants.
FGFs are a family of molecules that stimulate cell growth in many areas of the body, and are involved in the growth of multiple tissues and in growth that takes place at various stages of life. They have potent effects during embryonic, fetal and child development, and can modify the size and structure of particular brain regions. They are also involved in the repair of adult tissues after injury and may mediate the cross-talk between different cell types in the brain.
As a result, they can be seen as mediators of the property that neuroscientists call “neural plasticity” — the ability of the brain to adapt to stress, experience, disease and the effects of drugs.
The research group started their study by measuring levels of approximately 20,000 different kinds of messenger RNA in dissected brain samples from people who died from suicide, accidents and sudden medical causes. Messenger RNA levels are a measure of how active different genes are, and the researchers took care only to study brains that had no complicating factors that would have changed their mRNA levels at death.
The analysis was conducted on samples from two areas of the brain involved in the coordination of thinking and emotion: the dorsolateral prefrontal cortex and the anterior cingulate cortex. Both are located toward the front of the brain behind the forehead. Previously, brain scan studies have found differences in brain activity levels and size in these areas in people with psychiatric illnesses.
In the current paper, the researchers report what they found when they zeroed in on a group of six kinds of related mRNA that had the most coordinated differences between the samples from depressed brains, the non-depressed brains and the bipolar brains.
These turned out to be mRNAs for four different FGF molecules and two receptors that bind to FGF and are key to their function. Levels of all of the mRNAs encoding these proteins were lower in the brains of people with major depression. Lower mRNA levels mean the brain may not produce enough protein to carry out normal function.
The team confirmed its finding using another genetic technique called PCR analysis, which revealed that the most significant differences were in levels of mRNA for one of the FGFs, called FGF1, and for the two receptors, FGFR2 and FGFR3.
The researchers emphasize that they do not yet know whether the depressed people were born with lower levels of these molecules, or whether the lower levels were brought on by the effects of depression on the brain or by external factors such as stressful events. Other studies have shown that genes involved in brain chemistry and stress response are expressed differently in the brains of depressed people and non-depressed people.
“We can't say whether these FGF gene expression changes are a predisposing factor for depression, or a consequence of the disease process itself,” says lead author and U-M research investigator Simon Evans, Ph.D. “There may be totally normal people out there with compromised FGF systems, but if they don't experience stressful life events they may never develop major depression. We need to study this system further to unravel this question.”
Even as they made their discovery, the researchers grasped the potential significance of the FGF finding. “It's a new direction for depression research to go,” says Evans. “Given the known roles of this FGF family in neural development and maintenance, it's not a huge leap to see how compromising the system could lead to changes in neural circuitry and contribute to mood disorders.”
“The bottom line is, the FGF system is less active in depressed individuals and presumably, correcting that would be part of how you can make them better,” says Akil, who is co-director of the U-M Mental Health Research Institute. “This finding gives us a new target and a new set of ideas for pursuing better treatment.”
Akil notes that the brains of bipolar people in the study did not show the decreased FGF gene activity. “This was all the more remarkable since both groups of individuals were severely depressed at the time of death,” she says. “This is yet another indication that bipolar illness, though classified with depression as a mood disorder, is biologically a very different disease.
The Pritzker Neuropsychiatric Disorders Research Fund L.L.C. has filed a patent application related to this research, but the research team has made all of its data on mRNA levels for all types of growth factors available on the Internet. These can be found with the paper on the PNAS web site, http://www.pnas.org.
With these results in hand, the research team hopes now to look at FGF levels in other areas of the brain including the hippocampus, and to look for differences in levels of other families of growth factors. They also hope to look at the different layers of the brain's cortex to see if there are any differences by layer. And, they hope to look at the genes that encode FGFs and their receptors, to see if slight differences in gene sequence could modify the activity level of these genes in the brain and contribute to the observed differences.
Akil also says it might be possible someday to study FGF differences in living people, if scientists can develop tools to measure levels of the FGF receptors using brain imaging such as positron emission tomography, or PET.
In addition to Evans and Akil, the study's authors are: from the University of Michigan, Stanley J. Watson, Juan F. Lopez, Robert C. Thompson, J. D. Stead, C.R. Neal and F. Meng; from UC Davis, P.V. Choudary and E.G. Jones, who communicated the article to PNAS; from Stanford's Human Genome Center, J.Z. Li and R.M. Myers; and from UC Irvine, M.P. Vawter, H. Tomita, D.M. Walsh, and W.E. Bunney. Several authors are members of the U-M Depression Center, the nation's first comprehensive center devoted to research, treatment, education and public policy on depressive disorders.
Reference: Proc. Natl. Acad. Sci. USA , 10.1073/pnas.0406788101 (open access paper -- http://www.pnas.org/cgi/reprint/0406788101v1.pdf)
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