Immune Activation and Autism

Finding the genetic pathways that drive autism spectrum disorder

May 2017

According to previous research (1), pregnant women who undergo immune activation by contracting a severe infection within their first two trimesters may stand an increased risk of their child developing autism spectrum disorder (ASD). But how are the two factors linked? To understand the connection, a new study aimed to investigate a possible pathway in mouse models (2).

“We were particularly interested in understanding to what extent maternal immune activation (MIA) would induce changes in the developing brain that are similar to, or overlapping with, changes found in the postnatal ASD brain,” says Tiziano Pramparo, lead investigator and assistant researcher in the department of neuroscience at University of California, San Diego. “Finding a certain degree of overlap would provide indirect evidence that there are shared etiological routes between MIA and ASD pathophysiology, thus potentially suggesting an increased risk in those pregnancies with a history of prenatal infections and hospitalization.”

The team began their investigation by looking into cortical development – and if MIA caused genetic changes in the processes behind it. After reanalyzing prior data on the topic (3), the researchers noted that alterations in developmental genes were similar to young ASD brains. After digging further and conducting their own study on mouse models, the investigators discovered an even closer link. “We identified the dysregulation of genes involved in protein production, and specifically those involved in the cap-dependent translation initiation gene,” says Pramparo.

“When we analyzed which set of genes were commonly altered in the cortical tissue between the MIA rodents and ASD postmortem brains, we found that the strongest signal was for genes with translation initiation functions – specifically EIF4E,” Pramparo says. “If one wanted to speculate and jump to conclusions, we could say that MIA-induced effects due to prenatal infections may lead to dysfunction of the machinery regulating the production of proteins, and this alteration is one of the potential causes underlying ASD.”

Pramparo appears confident enough to speculate, and has already applied for additional funds to investigate whether the pathway can be targeted with a specific blocker to ameliorate – or even reverse – any behavioral and cellular abnormalities induced by MIA.

With the beginnings of a success story in hand, Pramparo and his team plan to use the same prenatal model systems to discover any overlapping effects of Zika infections on genes that are important for cortical development – and whether certain types of Zika infections during pregnancy could also lead to an increased risk of ASD.

  1. HO Atladóttir et al., “Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders”, J Autism Dev Disord, 40, 1423–1430 (2010). PMID: 20414802.
  2. MV Lombardo et al., “Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder”, Mol Psychiatry, [Epub ahead of print] (2017). PMID: 28322282.
  3. DB Oskvig et al., “Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response”, Brain Behav Immun, 26, 623–234 (2012). PMID: 22310921.

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