Depression susceptibility passed down through sperm

Inheriting a vulnerability to depression from father to offspring in mice via RNA in sperm
16 February 2021

Interview with 

Rahia Mashoodh, University of Cambridge

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We look like our parents because we inherit DNA from each of them, and that DNA is the recipe book that controls how our bodies put themselves together when we’re embryos. But, it turns out that other traits can be transmitted from parents to their offspring too, but not directly in the DNA. Researchers in China have shown that male mice that become depressed can pass on an increased tendency for depression to their offspring. The scientists speculate that pieces of short-lived additional genetic material, made of a chemical relative of DNA called RNA, are added to the sperm in the depressed dads. When these sperm fertilise eggs, the RNA messages alter which genes are turned on and off early in the animal’s development, switching its susceptibility to depression. Rahia Mashoodh wasn’t part of the study but is involved in similar research at the University of Cambridge...

Rahia - So what they did was they took mice and exposed them to a chronic stressor. And what this did at the end of the 5 week period, these mice started to show what scientists would call sort of depression-like behaviour. Obviously mice don't get depressed in the ways humans do, but there are things we can test in mice that tell us that they are showing very similar symptoms. And so they do this and then they ask actually, can this experience be transmitted to the next generation? And they take females that don't have such an experience and they get mated with these males. And then they look at their offspring and their offspring seemed to be fine. If you have a depressed father, you have an offspring that seems to look like a normal, healthy, happy mouse. However, they seem to be predisposed to stressful stimuli. So for example, when you then expose them to a stressor, they start to show behaviour similar to their father so depression-like stressed behaviour.

Eva - I see, so essentially, if you stress out one of these mice, they're more likely to start having depression-like symptoms after maybe fewer stresses than a normal mouse might have?

Rahia - Exactly. What that suggests is that what these fathers have conferred is like an underlying variability to that stress-related behaviour.

Eva - How did they then go about figuring out how that was transmitted?

Rahia - So what they were interested in was the idea that maybe there's something in sperm that gets transmitted during development, because mouse fathers don't really participate in the care of their offspring. So what else could fathers be transmitting? They thought that it must be in the sperm. And so they look at what's called small non-coding RNA. And these are molecules that come from your genes, but basically have regulatory functions. So they bind to other genes and inhibit their expression, and so they can cause a wave of change. So what they decided to do is first look at what's in the sperm, and they found a bunch of changes in these small RNAs. And then they wanted to say: is what's in the sperm actually sufficient to cause the effects they see in offspring? And so they essentially did what's called artificial insemination, where they took the sperm, implanted it into an egg, and then implanted it into a mother. So the mother has no idea who she's mated with, and it just gets transmitted directly. And they found that again, in vitro fertilisation was sufficient to create offspring that were hypersensitive to stress. The crucial bit is that these experiments were performed in genetically identical individuals, and so the only thing that could vary is the expression of these RNAs.

Eva - How does stressing out a male mouse lead to different kinds of RNA in the sperm that he makes?

Rahia - One of the theories about this is that the sperm production happens in the gonad, and because stress can be so systemic, the stress hormones reach the gonads. And they then cause various effects along the sort of sperm track. And as they're traveling, they pick up all of these small RNAs... we still don't know.

Eva - Once the sperm with the depressive RNA reaches the egg, what does the RNA actually do in the egg to cause the effects in the embryo?

Rahia - These small RNAs - their entire function has to do with regulating gene expression. And so what these authors basically show is that when you inject these small RNAs, you're basically changing all of the gene expression - or the gene expression profile - of the developing embryo, and it's setting the trajectory of how that embryo will develop. And a lot of the genes that are being affected have to do with brain development and stress-related circuitry.

Eva - How many generations, then, did they track whether or not this effect was carried on? So - was it just in the babies, or the grandbabies, or the grand-grandbabies as well?

Rahia - What they find is that this only persists to their offspring. And so it's very short-lived.

Eva - How far can we say this might be true for humans too?

Rahia - There have been some studies looking at human sperm, particularly in the context of poor diet, showing that there are differences in the sperm that mirror some of these effects that we've just talked about. And so I think the capacity for them exists, but I think it's also important to remember that humans aren't lab mice, and so they live in very complex environments where there are many competing factors for these things. And so we don't really know when something like this would be transmitted or not. We're also slightly genetically different from one another, and so in these mice, because they're so identical, it is possible that these effects might be more prominent. And what we don't really know is how different underlying genotypes interact with these types of effects.

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