Maternal Immune Activation and Autism

Two new studies on the connection between the mother's immune system and autism popped up on Pubmed this morning.  Both studies use mice to demonstrate that a mother's immune being stimulated during pregnancy is capable of producing lasting the changes in her offspring.

The first study goes straight to the heart of the matter and demonstrates that mice born to a mother whose immune system was stimulated during pregnancy have problems in the three core areas of autism.  Or at least the mouse equivalent of the three core ares.

Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism.

 The core symptoms of autism are deficits in social interaction and language, and  the presence of repetitive/stereotyped behaviors. We demonstrate that behaviors related to these symptoms are present in a mouse model of an environmental risk factor for autism, maternal infection. We stimulate the maternal immune system by injecting the viral mimic poly(I:C) during pregnancy, and analyze the social and  communicative behaviors of the offspring. In one test, young pups respond to a brief separation from the mother with ultrasonic vocalizations (USVs). We find that, compared to pups born to saline-injected mothers, pups born to maternal immune activation (MIA) mothers produce a lower rate of USVs in the isolation test starting at day 8. The quality of the vocalizations is also different; analysis of sound spectrograms of 10day-old pups shows that male pups from MIA mothers emit significantly fewer harmonic and more complex and short syllables. These communication differences are also apparent in adult offspring. Compared to controls, adult MIA males emit significantly fewer USVs in response to social encounters with females or males, and display reduced scent marking in response to female urine. Regarding a second autism symptom, MIA males display decreased sociability. In a third test of characteristic autism behaviors, MIA offspring exhibit increased repetitive/stereotyped behavior in both marble burying and self-grooming tests. In sum, these results indicate that MIA yields male offspring with deficient social and communicative behavior, as well as high levels of repetitive behaviors, all of which are hallmarks of autism.

The second study, which is far more interesting to me, looks at what exactly the mother's immune does to her offspring.  The short answer here appears to be that it changes how genes are expressed in her offspring.  It effectively turns down the volume on many of the genes that are needed for proper neural development.

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. 

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS  function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given  an intraperitoneal (0.25mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4h, and levels decreased but remained elevated at 24h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.

The bottom line from both studies is that the mother's immune system, if suffficiently stimulated during pregnancy, is more than capable of producing some of the behavioral and biological symptoms of autism.  These results add to the existing literature that has found a relationship between maternal infections and mental disorders such as autism and schizophrenia.

So the next questions that needs to be addressed - the crucial ones - are whether the biological changes demonstrated in mice also happen in people and what is the catalyst that changes a routine event - maternal immune system activiation - into something else entirely.


References

1. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms  of autism. Brain Behav Immun. 2012 Jan 30. [Epub ahead of print]  PubMed PMID: 22310922 DOI: 10.1016/j.bbi.2012.01.011

2. Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. 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. 2012 Jan 30. [Epub ahead of print] PubMed PMID: 22310921 DOI: 10.1016/j.bbi.2012.01.015