Placental dysfunction is highly associated with abnormal fetal brain development and neurodevelopmental disorders such as autism. Penn recently demonstrated that a key placental neuroactive hormone—allopregnanolone (ALLO), a potent GABAA receptor agonist—is needed for normal cerebellar development and that its loss contributes to long-term neurological dysfunction, specifically ASD-like behaviors in male offspring1. Furthermore, ALLO replacement or muscimol (a GABAAR agonist) treatment in late gestation rescued this impaired behavior and the cerebellar white matter changes. However, excess ALLO exposure in utero for pups with normal placental function also resulted in ASD-like behaviors. This unexpected finding now leads to the proposed experiments (Aim 1) to define the molecular and cellular mechanisms underlying the convergent effects on neurobehavior, specifically ASD-like behavior when placental ALLO exposure is outside of the normal physiological range.
To assess whether there is a similar link between human placental neurosteroids and the later likelihood of autism (Aim 2), placental tissues from a unique cohort enrolled in a nationwide NIH-funded pregnancy study of nulliparous pregnancies (NuMom2b)2 who were recontacted for ASD risk assessment3 will be examined. Human placental neurosteroid production will be analyzed using a combination of placental neurosteroid gene pathway measurements plus measures of multiple neurosteroid levels, using gold-standard mass spectroscopy. Comparisons will be made between neurotypically developing offspring versus those at increased risk of ASD. A preliminary analysis of placental neurosteroids in pregnancy complications (preeclampsia, growth restriction, chorioamnionitis) will also be done.
These experiments will define mechanisms underlying these hormone-exposure induced behavioral changes, as well as how genetic mouse manipulations relate to human placental pathologies and ASD risk. Mechanistically defining the links between placental neurosteroids and elevated ASD risk in both mice and humans can support use of placental neurosteroid production as an early biomarker of increased ASD risk and provide a target for therapeutics aimed at decreasing this modifiable risk.