“Life moves pretty fast. If you don't stop and look around once in a while, you could miss it.” -Ferris Bueller
It is probably cliché at this point to mention that the world seems to be getting crazier/faster/more stressful. Stress can manifest in many different ways, including obesity, substance dependence, and depression. A new study led by Ronald Duman of Yale University has discovered how a particular gene regulates how the brain responds to stressors. The ability to regulate the expression of this gene could protect against neuronal damage. The results were published in the journal Nature Medicine.
Depression is much more than just feeling down about things; it can actually cause changes to the brain over time. Major depressive disorder (MDD) and stress have been associated with atrophy of neurons. Stress is believed to increase expression of the REDD1 gene that in turn inhibits mTORC1. The function of mTORC1 is to regulate protein synthesis based on nutrients and energy. Increased levels of REDD1 have been shown to reduce synaptic connections in the brain, which can bring on symptoms of depression.
The researchers eliminated REDD1 from mice and exposed them to stressful situations. They found that the mice kept their synaptic connections and were more similar to the control group that hadn’t been exposed to stress than the wild-type group that sustained damage from prolonged stress. The mice with the REDD1 knockout were able to be exposed to stress without showing signs of neuronal damage. Without REDD1, the mTORC1 pathway was not inhibited. Other mice had REDD1 overexpressed, leading to a greater risk of depression symptoms and more synaptic connections were lost.
Ketamine is a drug with a wide variety of medicinal uses, including some success as an anti-depressant. In proper doses, it can actually activate the mTORC1 pathway. This allows mTORC1 to produce the proteins needed to rebuild lost synaptic connections. As the neuronal damage is reversed, symptoms of depression begin to subside.
There are currently anti-depressions based on ketamine that are in human clinical trials now. The connection made by Duman’s group between REDD1 and mTORC1 could give drug developers another avenue of molecular targeting. As up to 17% of American adults have MDD, a treatment based on this approach could not just alleviate depression symptoms, but actually reverse the damage itself.