A study by researchers at Nanjing University (NJU) demonstrated that in mice, depression-like phenotypes induced by paternal stress can be inherited by offspring through a causal role of microRNAs (miRNAs) in the father’s semen.
An understanding of the mechanism of epigenetic inheritance of depression may lead to the development of more effective antidepressant treatments, the authors reported in the February 10, 2021 edition of Science Advances.
“Depression is a debilitating illness with a profound impact on the quality of life of millions of people around the world, but due to stigma, lack of effective therapies and inadequate mental health resources, depression is often largely unsuccessful. diagnosed and untreated, âsaid study co-leader Xi Cheng.
The antidepressants currently available are therefore not satisfactory, hence the urgent need to discover the biological basis and heritability of depression and to develop safer and more effective treatments, said the professor and research director of the School of Life Sciences at NJU.
Depression is believed to be due to genetic predispositions interacting with environmental factors in some depressive patients, although its exact etiology remains unclear.
However, compared to known environmental factors like stress and endocrine abnormalities, little is known about the genetic risks of depression.
For example, the genes responsible for the onset of depression, which can be used to generate disease models in rodents or as potential treatment targets, have not yet been identified by genetic analysis.
The evidence that parental experiences can affect the phenotypes of offspring in an epigenetically inherited way has sparked interest in the genetic factors underlying risk for depression.
Epigenetic factors, including DNA methylation, histone modifications, and non-coding RNAs, can be transmitted through the germ line to induce parent-related phenotypes.
However, the function, mechanism, and extent of paternal epigenetic inheritance remain poorly understood, primarily because sperm have long been believed to simply deliver paternal DNA to the oocyte.
Recently, sperm RNA has been increasingly recognized as an additional source of paternal inheritance beyond DNA, with various species of sperm RNA being passed to the oocyte during fertilization, including miRNA.
Inherited miRNAs are known to participate in embryonic development and the transmission of parental phenotypes to offspring, but the precise mechanism by which sperm RNAs reshape the development of the offspring to transmit a paternally acquired phenotype remains unclear.
In the new study, researchers led by Chen and his fellow professors at the NJU School of Life Sciences Jing-Ning Zhu and Chen-Yu Zhang investigated the mechanism of epigenetic inheritance of depression, specifically the role of sperm miRNAs. in heredity and susceptibility to stress-induced depression. -like phenotypes in the offspring in a new pattern of depression.
“We established a chronic mild stress-induced depression (CMS) -type model, in which mice were subjected to three daily stresses, including wet cage, food deprivation, restraint, strobe lighting, inversion light-dark cycle, a tilted cage and a loud noise, âChen explained.
âAll of the constraints and / or sequences were applied at different times to avoid habituation and to add an element of unpredictability to the constraints,â he said. BioWorld Science.
They demonstrated that the first filial offspring (F1) born to founder males (F0) in the CMS model were susceptible to symptoms of depression at the molecular, neuronal and behavioral levels.
“We hypothesized that sperm miRNAs can receive signals from the paternal environment and then reshape their profiles to respond to environmental stress, the detailed mechanism of which remains unclear,” Chen said.
MiRNAs in particular show distinct expression patterns in F0 males in the CSM model and paternal depressive-like phenotypes are reflected in F1 offspring.
In addition, neutralization of abnormal miRNAs in zygotes by antisense strands has been shown to save depressive-like phenotypes acquired in F1 offspring born to F0 males in the model.
âThe antisense strands of miRNAs are chemically modified single-stranded oligonucleotides designed to specifically bind and inhibit mature miRNAs,â Chen explained.
“Rescue of abnormal miRNAs in zygotes by antisense strands restored depressive phenotypes acquired in F1 offspring born to F0 males in the depression model,” he said.
âTherapeutically, rescuing miRNA imbalance via IVF technology may offer a crucial dimension for the development of new antidepressant therapies, although more research is needed to replicate this, before it can come close to human medicine. . “
Alternatively, “markers of depression can be worn on sperm miRNAs, so if we could check the sperm miRNA profile to identify high-risk depression patients, this could guide reproduction, but again, this would require extensive research “.
Looking ahead, said Chen, âour next step will be to explore the potential roles of human sperm miRNAs in depression. We have already contacted several hospitals and started to assess the scope of ethical clearance to measure sperm miRNA profiles in patients with depression. “