A longitudinal examination of gut microbiota dysbiosis and neuro-behavioral phenotypes of poly(I:C)-maternal immune activation in a preclinical model of autism and schizophrenia.

内容摘要

Maternal immune activation (MIA) induced by polyinosinic/cytidylic acid [poly(I:C)] is a widely used approach to study how gestational inflammation affects neurodevelopment. For this reason, we aimed to describe the changes in gut microbiota and neurobehavioral phenotypes across the lifespan of the MIA offspring. We administered poly(I:C) on gestational day 12 to induce MIA in pregnant C57 mice. Subsequently, we conducted behavioral phenotyping, a neuropharmacological sensitivity test, a morphological analysis of dendritic branches and spines, and a gut microbiota assessment in male offspring. Here, we performed a longitudinal analysis of gut microbiota maturation across development in poly(I:C)-MIA offspring and integrated these findings with behavioral and neuronal morphology assessments relevant to ASD and schizophrenia. Our results show that MIA treatment induces an increase in the marble burying test, which assesses repetitive and persevering behavior related to obsessive-compulsive disorder, as well as decreased social interaction, anhedonia, sensitivity to the psychotomimetic drug amphetamine, and a reduction of dendritic branches and spines in the pyramidal neurons of layers II/III of the prefrontal cortex. We also observed infant gut dysbiosis on postnatal day (PD) 30. This condition is unrelated to maternal vertical transferences and persisted until early adulthood (PD57) and adulthood (PD100). Our results show that MIA is a consistent and robust preclinical model of ASD/SCZ that allows identifying symptoms and signs of these disorders, which agrees with epidemiological human evidence. Additionally, the gut dysbiosis induced by MIA could be permanent, and since it is not induced by vertical transference, it could be supported by the brain-gut-microbiota axis effects. Additional neuroimmune and microbiological studies, such as microbiota transplantation or antibiotic interference, are necessary to better interpret the effects observed in this study.