Depression: Gene-activating drug reverses symptoms in mice

Mental Health
New research shows that activating a gene that, in turn, boosts the activity of certain neurons involved in depression can reverse symptoms of the condition in male mice.
dna strand
By activating a single gene, researchers have reversed symptoms of depression.

Depression is “the leading cause of disability worldwide,” as more than 300 million people across the globe are living with the condition.

In the United States, major depressive disorder affects 6.7 percent of the population, including over 16 million adults.

Recently, more and more studies have been shedding light on the genetic and neurological mechanisms at play behind depression.

For instance, a pioneering study has uncovered 44 genetic locations that the researchers showed to have a link to a higher risk of the condition. Other studies have found that brain areas scientists link with reward and memory processing are different in those living with depression.

Zooming in on a single gene, a genome-wide association study appearing in 2015 found that a variant of a protein-encoding gene known as Sirtuin1 (SIRT1) correlates with a much higher risk of depression.

Now, new research finds that direct activation of this gene in the prefrontal cortex — a brain area we associate with complex thinking and planning of socially-appropriate responses — can reverse symptoms of depression in male mice.

Molecular behavioral neuroscientist and pharmacologist Xin-Yun Lu, Ph.D., is the corresponding author of the latest study. The researcher is also a professor in the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University.

Prof. Lu and her colleagues published their research in the journal Molecular Psychiatry.

SIRT1 activator has antidepressant effect

To test the impact of a SIRT1-activating drug in depressed mice, Prof. Lu and team knocked out the SIRT1 gene in male rodents and examined their reaction to a sweet drink that they would usually strongly prefer.

The researchers found that knocking out the gene reduced the number of mitochondria in excitatory neurons and decreased their excitation. Mitochondria are the so-called powerhouses of the cell, that is, tiny organelles inside cells that turn nutrients into energy.

Excitatory neurons, explain the researchers, are underactive in depression and do not communicate with each other correctly. These neurons seem to be “disconnected” in depression, says Prof. Lu.

The researchers depressed the rodents by subjecting them to “chronic unpredictable stress.” They did so by restraining the mice for 2 hours, pinching their tails for 15 minutes, subjecting them to constant light for 24 hours, keeping them in wet bedding for 24 hours, or tilting their cages. They also subjected the mice to 10-minute small electric shocks and social isolation.

As a result of the chronic stress, the male rodents that had the SIRT1 gene knocked out lost their interest in the sweet solution they usually preferred — a symptom scientists consider to be the equivalent of anhedonia in depressed humans. These rodents also exhibited signs of “behavioral despair” in the forced swim test.

However, when the researchers injected the prefrontal cortex of the male rodents with a SIRT1 activator they call SRT2104, they reversed these symptoms. The drug had an “antidepressant-like” effect, according to Prof. Lu. She and her colleagues conclude:

These results suggest that SIRT1 in [medial prefrontal cortex] excitatory neurons is required for normal neuronal excitability and synaptic transmission and regulates depression-related behaviors in a sex-specific manner.”

Prof. Lu now plans to examine existing drugs and see if any of them affect SIRT1 in a similar way to the activator they used in this research. The scientists theorize that we may one day use SIRT1 activators as an effective treatment for major depression.

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