Sperm microRNAs confer depression susceptibility to offspring

Abstract

Evidence that offspring traits can be shaped by parental life experiences in an epigenetically inherited manner paves a way for understanding the etiology of depression. Here, we show that F1 offspring born to F0 males of depression-like model are susceptible to depression-like symptoms at the molecular, neuronal, and behavioral levels. Sperm small RNAs, and microRNAs (miRNAs) in particular, exhibit distinct expression profiles in F0 males of depression-like model and recapitulate paternal depressive-like phenotypes in F1 offspring. Neutralization of the abnormal miRNAs in zygotes by antisense strands rescues the acquired depressive-like phenotypes in F1 offspring born to F0 males of depression-like model. Mechanistically, sperm miRNAs reshape early embryonic transcriptional profiles in the core neuronal circuits toward depression-like phenotypes. Overall, the findings reveal a causal role of sperm miRNAs in the inheritance of depression and provide insight into the mechanism underlying susceptibility to depression.

Angiogenin mediates paternal inflammation-induced metabolic disorders in offspring through sperm tsRNAs

“…Increasing evidence indicates that paternal environmental inputs can affect the metabolic phenotype of the next generation through remodeling of the epigenetic blueprint of sperm. Recently, zygotic injection of total RNAs from isolated sperm or a subset of sperm small non-coding RNAs (sncRNAs) provided direct causal evidence for a role of a ‘sperm RNA code’ for the intergenerational transmission of paternally acquired phenotypes 1 – 9 . Sperm show dynamic changes in the composition of sncRNAs during the transition from the caput epididymis to the cauda epididymis, where sncRNAs are acquired via epididymosomes 4 , 10 , 11 .…”

The roots of paternal depression: Experienced and nonexperienced trauma or Folie a Deux?

“…These changes in expression and the phenotypic abnormalities observed in offspring were associated with altered histone methylation levels at genes in sperm (Siklenka et al, 2015). Another epigenetic mechanism that may transmit paternal life experiences to the future father, enhancing his risk for depression are microRNAs, as shown in a recent animal model study (Wang, Chen et al, 2021).…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…There is accumulating evidence indicating a significant miRNA contribution to depression, anxiety, and antidepressant action (28,29). A recent preclinical study showed that upregulated miRNA in the sperm of patients with depression significantly inhibited the expression of key genes in the pathway (30). In another study, miRNA-26a-3p was reported to be a putative modulator of antidepressant response (31).…”