Cutting Edge: Critical Roles for Microbiota-Mediated Regulation of the Immune System in a Prenatal Immune Activation Model of Autism

Abstract

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome-immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

“…Given the strong male-specific bias in the appearance of autism like phenotypes in the progeny following MIA [11,12], we were interested in whether there were sex-specific differences in the basal levels or the MIA-induced alterations of tRFs or microRNAs. No tRFs or microRNAs display sex-specific expression at any time point during normal gestation from E12.5 to E18.5 (Fig.…”

“…To trigger systematic maternal immune activation during pregnancy, we treated pregnant mice with poly(I:C), a viral RNA mimetic, at E11.5 and E12.5, as previously described [11]. Importantly, this poly(I:C) treatment regimen promotes the development of autism-related phenotypes in the MIA-offspring [10][11][12][13][14][15]. Maternal-fetal interface (placenta/decidua) samples were collected at various time points (3, 6, 12, 24, 48, 144 hours) after the second injection at E12.5 ( Fig.…”

“…Mice were treated similarly as previously described to trigger robust MIA [11,101]. Mice were mated overnight and the presence of a vaginal plug was designated as E0.5.…”

“…Among the many environmental risk factors for ASD, infection-associated MIA (maternal immune activation) during pregnancy poses a strong risk factor for ASD in subsequent generations [4,[7][8][9] and has been recapitulated in animal models. For example, MIA-induced ASD can be modeled in mice by treating pregnant mothers with the viral mimetic polyinosinic:polycytidylic acid (Poly(I:C)) [10][11][12][13][14][15]. Poly(I:C) treatment induces systemic inflammation during pregnancy and, as a result, offspring from Poly(I:C)-treated dams develop many of the defining features of ASD.…”

“…Poly(I:C) treatment induces systemic inflammation during pregnancy and, as a result, offspring from Poly(I:C)-treated dams develop many of the defining features of ASD. The MIA-triggered ASD phenotypes were found to be regulated by maternal immune pathways during gestation [10][11][12][13][14][15], suggesting close interaction between mother and the fetus. Such interaction takes place at the maternal-fetal interface, where fetal-derived placenta is bathed in the materal-derived decidua [16].…”