Researchers have reported that male mice showing depression-like behaviours were able to pass those traits onto their offspring, specifically through genetic material encoded within their sperm.
Depression is one of the most common and debilitating mental illnesses worldwide. Despite decades of research, the aetiology largely remains unclear. The general view is that genetic predispositions interact with environmental factors to initiate depressive episodes. While a lot is known about the environmental factors (e.g., stress), our knowledge about the genetic risks lags behind. Also, the specific genes responsible for the onset of depression that can be used to generate disease models have not yet been identified. In recent years, evidence has emerged that suggests parental life experiences can impact offspring phenotypes in an epigenetically inherited manner.
Sperm RNA is increasingly recognised as an additional source of paternal hereditary information beyond DNA. A diverse set of RNA species present in sperm can be passed into the oocyte upon fertilisation. However, the precise mechanism by which sperm RNA may reshape offspring development remains unclear.
In this study, published in Science Advances, researchers established a depression-like model by exposing male mice to unpredictable mild stresses daily for five weeks. These mice displayed a number of behaviours and physiological changes that represent depression. For example, these mice showed less interest in food and had heightened levels of stress-related hormones.
The team found that F1 offspring born to F0 males of the depression-like model were susceptible to depression-like symptoms. The team found this was the case at the molecular, neuronal and behavioural levels. They specifically found that sperm small RNA and microRNAs exhibited distinct expression profiles in F0 males, which were recapitulated in their offspring. Neutralisation of these abnormal miRNAs in zygotes by antisense strands rescued the acquired depression-like phenotypes in F1 offspring.
Overall, these findings reveal a causal role of sperm miRNAs in the inheritance of depression. They also provide insight into the potential mechanism underpinning susceptibility to depression. Most importantly, these results may pave the way to developing new treatments.
Study lead Xi Chen stated:
“Our findings may offer a new dimension for the development of novel antidepressant treatments. For example, we showed that rescue of miRNA imbalance in zygotes can reverse the acquired depressive phenotypes in offspring born to depressed fathers. Since the sequences and biological functions of many miRNAs are conserved between humans and mice, it is intriguing to investigate if sperm miRNAs also play a role in the inheritance of human depression and can be employed as a therapeutic target.”
Image by sibya from Pixabay.