Abstract
Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.
Highlights
Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring
Using the psychedelic 5-HT2A receptor (5-HT2AR) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as a pharmacological tool, we already reported that DOI-induced head-twitch behavior was augmented in adult mice born to influenza virus-infected mothers, as compared to control adult mice born to mock-infected mothers[29]
As expected, our findings here show that both head-twitch behavior induced by DOI (0.5 mg/kg) (Fig. 2A) and frontal cortex 5-HT2AR density as measured by radioligand binding assays with the 5-HT2AR antagonist [3H]ketanserin (Fig. 2B) were significantly increased in adult maternal immune activation (MIA)-mice, as compared to adult mice born to mock-infected mothers
Summary
Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Recent preclinical findings suggest that MIA in mice produces dysbiosis of the intestinal microbiota[18,19,20] and abnormal behavioral phenotypes in offspring[18,21] This accumulating evidence supports the existence of altered gut-brain physiological pathways in both MIA models and neurodevelopmental psychiatric conditions. Using maternal infection with a mouse adapted influenza A/WSN/33 (H1N1) virus as a preclinical MIA model (Fig. 1), here we asked whether manipulation of the gut-brain axis could serve as a novel approach to reduce transition to MIA-induced phenotypes, including dysregulation of frontal cortex 5-HT2AR density and altered performance in behavioral models of psychosis and cognition
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