One way chronic stress appears to cause depression is by increasing levels of a protein in the brain that decreases the availability of an important chemical that regulates our mood, scientists report.
High TG2 levels in the mouse translated to atrophy of neurons, depression-like symptoms and reduced levels of TrkB, the receptor for brain derived neurotrophic factor, a brain-nourishing molecule that also aids connectivity, said Dr. Anilkumar Pillai, neuroscientist in the Department of Psychiatry and Health Behavior at the Medical College of Georgia at Augusta University.
When scientists overexpressed TrkB, it relieved the depression-like symptoms in their animal model. “If you don’t have enough BDNF, then all the serotonin in the world won’t help,” said Pillai, corresponding author of the study in the Nature journal Molecular Psychiatry.
Likewise, when they directly reduced TG2 levels using a drug or a viral vector, more BDNF signaling occurred and depressive symptoms abated, said Pillai, who suspects that the protein may be a powerful new target in the fight against depression.
They found TG2 levels increased in their animal model following administration of stress hormones and after several weeks of actual stress that mimics the lives of chronically stressed individuals. Both produced classic depressive behavior and increased TG2 levels in the prefrontal cortex, a region involved in complex thoughts, decision-making as well as mood and personality expression.
Serotonin is a major neurotransmitter in the brain involved in many functions, including mood regulation. Serotonin levels in a depressed patient’s blood should be high because serotonin signaling in the brain is low, Pillai said. Blood levels can be used to help diagnose the condition that affects about 350 million people worldwide and is the leading cause of disability, according to the World Health Organization. Many cell types make serotonin. Interestingly, the vast majority of serotonin is made in the gut, but neurons do make some of their own, Pillai said.
Astrocytes make BDNF, whose levels are also low in depression. Although just how the two work together is an unfolding mystery. In this study, Pillai and his team further linked them by showing that treatment that increases serotonin availability — as most antidepressants do — also increased levels of the BDNF receptor thru the action of RAC1. TG2 converts serotonin to RAC1, a protein that helps rejuvenate the BDNF receptor, TrkB.
Now the MCG scientists have shown that in depression a healthy balance of all these is upset, as elevated TG2 makes less serotonin available, leaving insufficient levels to enable proper communication between neurons. The brain also is more vulnerable as the increased level of activated RAC1 is inexplicably degraded, which leads to less instead of more BDNF signaling.
“Increased amounts of TG2 will eventually lead to decreased levels of RAC1, and BDNF signaling is just not happening,” Pillai said.
Next steps include looking for other drugs that lower TG2 levels. For the study, researchers used cysteamine, whose clinical uses today include treatment of a rare genetic condition in which a buildup of crystals can cause kidney failure. Unfortunately, the drug creates an odor that has patients bathing multiple times daily. They also want to directly measure serotonin levels following treatment, although Pillai notes that increased BNDF signaling should be significant to alleviate symptoms. Original Article
Everyone occasionally feels blue or sad. But these feelings are usually short-lived and pass within a couple of days. When you have depression, it interferes with daily life and causes pain for both you and those who care about you. Depression is a common but serious illness. Many people with a depressive illness never seek treatment. But the majority, even those with the most severe depression, can get better with treatment. Medications, psychotherapies, and other methods can effectively treat people with depression.Some types of depression tend to run in families. However, depression can occur in people without family histories of depression too. Scientists are studying certain genes that may make some people more prone to depression. Some genetics research indicates that risk for depression results from the influence of several genes acting together with environmental or other factors. In addition, trauma, loss of a loved one, a difficult relationship, or any stressful situation may trigger a depressive episode. Other depressive episodes may occur with or without an obvious trigger.This introductory course provides an overview to the various forms of depression, including signs and symptoms, co-existing conditions, causes, gender and age differences, and diagnosis and treatment options.
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