The transgenerational effects of prenatal immune activation?

The paper by Ulrike Weber-Stadlbauer and colleagues [1] provides some food for thought today with the suggestion that the concept of prenatal immune activation might have consequences further than just to exposed offspring.

For those not familiar with the concept of prenatal immune activation, it refers to the process(es) that occur following "exposure to infectious or inflammatory insults" during the nine months that made us. As you'll probably be aware, our nine months of watery 'captivity' is an important time in making us who we are. It is also a time when we are unfortunately vulnerable to quite a few factors that can adversely affect our stay in the womb (see here and see here for examples) and indeed, that can have repercussions for our future development and wellbeing. Among the vast number of agents that can and do affect pregnancy, various infectious agents (such as viruses and bacteria) that have been with humankind since the year dot play a prominent role; either through their own actions or via what biochemical processes they initiate as a mother's body seeks to protect itself and its unborn child. In short, the maternal immune system might itself, at this crucial time of reprogrammed immune tolerance, exert a less than positive effect on the foetus as a result. The sorts of outcomes potentially linked to exposure to this prenatal immune activation are varied to say the least (see here).

Weber-Stadbauer et al looking at a mouse model of prenatal immune activation - that's MOUSE model - took things one stage further by asking whether effects of such immune activation exposure might persist beyond just one generation of offspring. So: "Using an established mouse model of prenatal immune activation by the viral mimetic poly(I:C), we show that reduced sociability and increased cued fear expression are similarly present in the first- and second-generation offspring of immune-challenged ancestors." Further: "These transgenerational effects are mediated via the paternal lineage and are stable until the third generation, demonstrating transgenerational non-genetic inheritance of pathological traits following in-utero immune activation."

When the authors suggest that their results "demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations" they aren't kidding. Indeed, accompanied by the rise and rise of research talking about transgenerational inheritance not primarily mediated by more traditional structural genetics (as far as we know) the possibilities are truly endless if said processes are indeed transferable from mouse to humans.

But just before we do get too carried away, let's be a little cautious. Aside from the fact that mice are mice and not humans (see here) and that complex behaviours like human sociability are probably not best served by looking solely at mice, these data need to be independently replicated. I note from other research by members of this authorship group [volumes of research it has to be said] the interest in how a label like 'schizophrenia' (or should that be schizophrenias?) might have a 'developmental neuroinflammation' element to it [2] implies that priming of the immune system should be something that is detectable (see here) and hence potentially amenable to change. Indeed, this may very well tie into the increasingly popular idea that immunopsychiatry is here to stay (see here). I would therefore, like to see a little more on how prenatal immune activation presents in immune system terms down the generations over and above "unique and overlapping genome-wide transcriptional changes in first- and second-generation offspring of immune-challenged ancestors." Does, for example, this imply that there is a potential biomarker set consisting of biochemical, epigenetic and transcriptional data that might characterise those at risk of such consequences? And indeed, are we all potentially the result of our grandmother's immune experiences as we might be her dietary patterns?

To close, following the sad news that Gareth 'Blake's 7' Thomas has died, that theme tune...

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[1] Weber-Stadlbauer U. et al. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Mol Psychiatry. 2016 Mar 29.

[2] Meyer U. Developmental neuroinflammation and schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2013; 42: 20-34.

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Weber-Stadlbauer U, Richetto J, Labouesse MA, Bohacek J, Mansuy IM, & Meyer U (2016). Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Molecular psychiatry PMID: 27021823