Why does the same inflammation affect some fetuses but not others?

To understand how autism spectrum disorder, or ASD, develops, researchers study how the prenatal environment influences neural development alongside genetic factors. One area of investigation is the maternal immune response during pregnancy. Animal experiments have explored pathways through which stimulating the mother's immune system can affect brain development and behaviour in offspring as they grow. Background study ↗

The new study from Cold Spring Harbor Laboratory is part of this line of research. Its authors asked why some fetuses are affected while others developing in the same mother are not. The higher rate of ASD diagnosis in boys also provides a reason to investigate sex differences. Research institution's explanation ↗

What this study directly examined, however, was not ASD-related behaviour after birth, but changes in fetuses and placentas within 24 hours of an immune stimulus. By following those differences, the researchers sought to investigate part of the pathway through which neural development may be affected. Original paper ↗

Pregnant mice were given a substance that mimics the immune response to a viral infection. Within 24 hours, around 30% of the fetuses showed developmental abnormalities involving body weight and sensory organs, among other measures. Under these conditions, abnormalities occurred in a subset of males; the other males and the females did not show the same changes.

The placentas of the affected fetuses also changed. Expression of inflammation-related genes increased in cells including those at the maternal–fetal interface, placental structure was disrupted, and immune cells and cytokines accumulated in the amniotic fluid. Original paper ↗

An important point in interpreting these findings is that the placenta is not simply a barrier through which inflammation passes.

In an earlier mouse study, deleting the IL-6 receptor from placental trophoblast cells reduced fetal brain inflammation and later behavioural and cerebellar abnormalities following maternal immune stimulation. The response within the placenta influenced the effects on the brain downstream. 2017 study ↗

Read alongside the new findings, this raises a question: what distinguishes individuals whose placentas maintain their function during inflammation from those whose placental function breaks down?

Is it the ability to limit an immune response? The capacity to preserve tissue structure? Differences in the course of development? Sex offers a clue, but being male did not determine the outcome on its own.

Even within the same mother, fetuses do not necessarily experience the same local environment or respond to a stimulus in the same way.

Why do some placentas retain their function while others develop inflammation and structural disruption? Explaining that difference could bring us closer to understanding what determines developmental effects beyond whether maternal inflammation is present or absent.

When considering individual differences in neural development, how should we connect the properties of the brain itself with the responses of the tissues around it? That is the question we want to pursue from this study.