From Father to Offspring: Paternal Transmission of Depressive-Like Behaviors

Major depressive disorder is a common and disabling disorder with an overall lifetime risk estimated to be ∼15% in the general US population. Depression is thought to be caused by a combination of genetic and environmental factors. Indeed, a rich literature has demonstrated that depression is highly heritable, with roughly 40% of the risk being genetic (Sullivan et al, 2000). More recently, there has been interest in the possibility that epigenetic mechanisms might also contribute to the transgenerational transmission of stress-induced vulnerability.

In adult male mice, exposure to chronic social defeat stress induces a syndrome of behavioral deficits that closely model subtypes of human depression (Krishnan et al, 2007). We hypothesized that these behavioral adaptations might be transmitted to subsequent generations, ultimately leading to enhanced susceptibility to depressive-like behaviors in the offspring of mice sired from defeated fathers. Using social avoidance as a measure of depressive-like behavior, our initial findings confirmed that male mice bred from defeated fathers, but not from control fathers, showed pronounced social avoidance when subjected to submaximal defeat stress (Dietz et al, 2011).

To further study the role of paternal influences in heritability of depressive-like behaviors, we performed a ‘pre–post experiment,' which allowed us to directly compare both male and female offspring sired from the same males before and after having been subjected to social defeat. We performed a battery of behavioral tests (forced swim test, elevated plus maze, sucrose preference, and social defeat) that together examine depressive- and anxiety-like behaviors. Compared with pre-defeat offspring (which were indistinguishable from controls), both male and female offspring from the defeated fathers demonstrated robust depressive- and anxiety-like phenotypes. The offspring of defeated fathers also displayed increased basal levels of plasma corticosterone and decreased levels of vascular endothelial growth factor, both of which have been implicated in depression and antidepressant action (de Kloet et al, 2005; Warner-Schmidt and Duman, 2008).

In the final set of experiments, to directly assess the role of epigenetic mechanisms, we used in vitro fertilization (IVF) to investigate whether the behavioral phenotypes observed in the above experiments were directly transmissible through the sperm of socially defeated mice. Sperm from defeated and control mice were used to impregnate female mice, and the offspring were tested for depressive- and anxiety-like behaviors. Unlike our previous findings, animals derived using IVF from defeated fathers did not show a robust increase in susceptibility for a depressive- or anxiety-like phenotype, with only very modest differences seen.

Together, our studies demonstrate the clear transmissibility of depressive- and anxiety-like phenotypes to the F1 generation offspring of socially defeated mice. Our IVF experiments indicate that most of this transgenerationally transmitted behavioral phenotype likely occurs through behavioral mechanisms. Nevertheless, our data suggest that a small contribution of epigenetic modifications is possible, which now requires further examination. These and related (Franklin et al, 2010) findings in mice raise the possibility that part of an individual's risk for clinical depression or other stress-related disorders may be determined by his or her father's life exposure to stress, a provocative suggestion that now requires direct study in humans.

The authors declare no conflict of interest.