FGF9 – Depressed Brains Are Filled With This Protein

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Plenty of research into the causes of depression focuses on what the brain lacks. However, a new study is one of the first to suggest that having too much of an essential component may trigger depression.

When researchers studied the donated brains of depressed people who has been diagnosed with major depression, they found 32 percent more of a protein called fibroblast growth factor 9, or FGF9, in a key part of their brain than people without the condition.

They also found that raising FGF9 levels artificially in rats led to depression-like behavior changes, and repeated social stress caused brain FGF9 levels to rise.

Taken together, the findings provide more evidence that depression is a physical illness.

If FGF9 or its effects prove to be a good target for drugs, the finding could eventually help lead to better medications for the condition.

FGF9’s role was discovered by a team from the University of Michigan Medical School and the Pritzker Neuropsychiatric Disorders Research Consortium. They made the discoveries through years of detailed comparisons of brain tissue donated by people with and without depression, and multiple studies in rats.

Because drugs that block excess production of something in the body generally cause fewer side effects than drugs aimed at increasing something, the team says their findings could hold promise for the development of a new class of antidepressants.

Co-first author Elyse Aurbach, neuroscience doctoral student, says:

“Fixing depression is not easy, because it’s a disorder at the level of the circuits that connect brain cells, and many regions of the brain are involved. Still, this is the first time FGF9 has been identified as related to depression, and found to be active in a critical area of the brain for the disorder. We and others need to study it further to determine what is going on. It’s very exciting.”

36 Depressed Brains

They made the finding using postmortem brain samples from the brain bank at the University of California, Irvine, supported by the Pritzker Consortium. It includes 36 depressed and 56 non-depressed brains.

Through three different kinds of microarray gene expression studies and a confirming test called quantitative PCR, they looked at all the genetic activity that was going on when these brain donors died, specifically in the area of the brain called the hippocampus.

The hippocampus is a crucial area of the brain for memory, learning, and stress control. It has been found to be smaller in people with depression, and this is thought to be the result of chronic stress that affects the health of brain cells in that region.

Each experiment showed higher FGF9 levels in the depressed brains. What’s more, the levels of several other fibroblast growth factors were down when FGF9 was up, suggesting the entire system for regulating cell growth and development in the brains of depressed people was altered.

Rat Anxiety

Intrigued by the human results, the team decided to explore FGF9’s role further through experiments with rats. This allowed them to do something they can’t do in humans: try to determine if FGF9 rises in response to something, such as stress, or if levels are naturally higher and predispose someone to depression.

First, they exposed rats to repeated social stress over a week and a half, and looked at the levels of FGF9 in various regions of the brain’s hippocampus. Not only did the levels rise, but the rats got more socially withdrawn and less likely to maintain a healthy weight.

Next, they looked at what happens if FGF9 is injected into the brain—specifically, the ventricle, or open space between the brain’s two sides. Other rats received a placebo. The rats that got the FGF9 acted more anxious, and moved around less—and these depression-like changes persisted with repeated injections.

Lastly, the group created a virus that interfered with FGF9 production through a process called RNA interference. They injected it, or a comparison virus that didn’t block FGF9 production, into rats’ brains—in a specific area of the hippocampus called the dentate gyrus.

The active virus caused levels of FGF9 to drop about 30 percent, while other FGF molecule levels stayed the same.

And the rats showed less anxiety.

Better Antidepressants?

Huda Akil, a professor of psychiatry and neuroscience and Aurbach’s mentor, says:

“We call this approach ‘reverse translation’. We start by careful, broad scale analyses in the human brain to discover new molecular players that might play a role in triggering or maintaining the depression.

We then follow them up in rodent studies to understand the role of these molecules and determine whether we can target them for new treatments.”

Aurbach, Akil, and colleagues are already performing more experiments to determine why FGF9 production rises, as well as to study it in other brain regions and to see how it affects communication among brain cells. A patent application has been filed and is being managed by the Pritzker Consortium.

They hope their work will lead to a search for medications to affect FGF9 levels, but caution that the molecule is important in the lungs and blood vessels, too.

Reference:
  1. Elyse L. Aurbach, Edny Gula Inui, Cortney A. Turner, Megan H. Hagenauer, Katherine E. Prater, Jun Z. Li, Devin Absher, Najmul Shah, Peter Blandino Jr., William E. Bunney, Richard M. Myers, Jack D. Barchas, Alan F. Schatzberg, Stanley J. Watson Jr., and Huda Akil
    Fibroblast growth factor 9 is a novel modulator of negative affect
    PNAS 2015 ; September 8, 2015, doi:10.1073/pnas.1510456112

Last Updated on October 14, 2023