Japan – Depression is a mental disorder that affects over 300 million people globally. While treatments exist, many of them are based on one hypothesis of how depression arises. Patients that do not fit in this mold may not be receiving the related benefits. A study led by Hiroshima University (HU) published online this May in Neuroscience, shed light on how one protein called RGS8 plays a role in depression behaviors.
Scientists think depression is caused by monoamine hypothesis, the type of two chemicals that depressed people lack: serotonin and norepinephrine (NE). Ninety percent of antidepressant drugs are made based on this idea. They aim to recalibrate these two monoamines. For some of these patients, however, it may not be enough.
“Thirty percent of people on these drugs do not experience any effect,” said Yumiko Saito and Yuki Kobayashi, neuroscientists at HU’s Graduate School of Integrated Arts and Sciences.
This study builds upon previous work in which the team found that RGS8 controls a hormone receptor called MCHR1. Parts of the brain involved with movement and mood regulation show signs of RGS8 expression. MCHR1, when active, helps regulate sleep, feeding, and mood responses. The researchers found that RGS8 inactivates MCHR1 in cultured cells.
Therefore, less RGS8 can lead to increased depressed behavior. Here, the team studied depression in mice at the behavioral and immunohistological level.
First, the mice did a swim test, which is a common behavioral analysis method to assess depressive behaviors in animals. Researchers measure the time each mouse was active, then subtract it from the total test time, leaving researchers with an immobility time.
Mice with more RGS8 in their nervous system recorded shorter immobility time than those with a normal amount of RGS8. When given an antidepressant drug that acts on monoamines the RGS8 mice had even shorter immobility time. However, when the mice were given a drug that stops MCHR1 from working, immobility time did not change.
“These mice showed a new type of depression,” Saito remarked. “Monoamines appeared to not be involved in this depressive behavior. Instead, MCHR1 does.”
With that conclusion, the team looked at the mice’s brains under the microscope to determine the relationship between MCHR1 and RGS8. More specifically, they examined the size of cilia sprouting from cells in a region of the hippocampus called the CA1, where RGS8 concentration was highest. Cilia are TV antennae-like organelles involved in cellular communication.
The team found that RGS8 mice not only had less depressed behavior than those without extra RGS8, but they also had longer cilia. That is, mice that took the drug that stopped MCHR1 from working had longer cilia.
In the past ten years, scientists have witnessed a correlation between dysfunctional cilia and disorders like obesity, kidney disease and retina disease. However, not much is known about their relationship with mood disorders. Hence, these led the team to think that RGS8 is a promising candidate toward the development of new antidepressant drugs, which is a focus for future experiments.