Susceptibility to Depression Can Be Transmitted From Father to Offspring in Mouse Model

Chinese researchers from Nanjing University have shown that depression is heritable in mice. However, no genes have been identified.

Depression

Depression is one of the most common mental illnesses, and in light of the Covid 19 pandemic, doctors fear that its rates are increasing. Scientists have not yet identified the exact etiology of this disease, but it is thought to result from an unfortunate mix of environmental factors, such as stress, and genetic predisposition. In fact, depression often affects members of the same family, and depressive episodes in one parent can affect that parent’s offspring. However, a depression gene has not yet been identified.

A growing number of studies suggest that depression is not inherited genetically, but rather epigenetically. Epigenetics is the study of factors that alter the expression of genes, but not their sequence. For example, DNA methylation, changes in histones, and the activity of non-coding RNAs are epigenetic factors that are altered by environmental factors and affect gene activity.

A new study published in Science Advances, conducted at Nanjing University in China, shows how environmental factors, including stress, can be transmitted through small RNAs.

Offspring likely to develop depression if the father had the disease

The first step in this research was to make the mice depressed. To do this, the scientists exposed the male mice to low but repeated and unpredictable stress for five weeks. At the end of those five weeks, the mice lost weight and became apathetic and anhedonic compared to other mice. Their plasma corticosterone levels, a hormone produced under stress, were particularly high.

These depressed males mated with completely healthy females. When the mice reached adulthood, the behavior of their offspring was analyzed. At first glance, there were no signs of depression. However, when the mice of the depressed male were exposed to mild stress for two weeks, they developed the same range of symptoms as their progenitor. Thus, the depressed male mouse has passed on a greater susceptibility to this mental illness to its offspring.

Noncoding RNAs may be the culprits

If genes are not involved, what is the mechanism by which susceptibility to depression is passed on? In the study, the scientists have set out to focus on noncoding RNAs. Those present in sperm are passed to the embryo at the time of reproduction. So the scientists extracted and isolated all the RNAs from sperm cells and injected them into a zygote. The zygote is implanted into a mouse, which then gives birth to the offspring. The resulting mice were also more sensitive to stress-induced depression.

By refining their experiments, the scientists identified which RNAs are responsible for depressive states. These are microRNAs of about 20 nucleotides; 19 types of these small molecules have been identified in sperm. It turned out that in depressed men, 16 of them have a tenfold increased activity compared to healthy mice. This overactivity alters neural circuit development during embryonic development and mediates stress sensitivity that leads to depression.

A clue for studying depression causes in humans

These results perfectly describe how an environmental factor, namely stress, and a depressive state, can be passed on to offspring through a pathway other than genes. Can these observations shed light on depression in humans?

“Since research with mice is not always transferable to humans, I cannot say now that our results are transferable to humans,” says Xi Chen, a researcher at Nanjing University in China and the leader of her research. However, because the sequences and biological functions of many microRNAs are conserved between humans and mice, it is interesting to investigate whether microRNAs in sperm also play a role in the inheritance of human depression. Indeed, our next step is to explore the potential role of human sperm microRNAs in depression.

If this turns out to be true it will allow for a new approach for treating depression or at least help predict those likely to develop depression based on the history of their fathers.