ABSTRACT Compromised placental function is highly associated with abnormal fetal brain development, and later with neurodevelopmental disorders such as autism, epilepsy, and schizophrenia, but the causal mechanisms remain largely unknown. The prevalence of these neurodevelopmental disorders is increased in those born preterm or born after pregnancies with evidence of poor placental function. Altered cortical GABAergic signaling has been implicated in many neurodevelopmental disorders, but until recently the tools to examine the relationship between placental dysfunction, altered cortical development and GABAergic signaling did not exist. In the initial funding period of this proposal, we validated and used our novel mouse model to directly demonstrate for the first time that a key placental hormone-- allopregnanolone (ALLO)-- is needed for normal brain development and that its loss contributes to long-term neurological dysfunction. ALLO is a potent GABAergic neurosteroid derived from progesterone that is made predominantly by the placenta in both rodent and human late gestation, resulting in high fetal brain concentrations of placentally-derived ALLO. Deleting the gene encoding the ALLO synthesis enzyme only from the placenta resulted in decrease in gestational ALLO exposure and produced global, yet sex-linked and regionally-specific, changes neuroanatomy and behavior. Reduced placental ALLO production impaired prenatal somatosensory corticogenesis and upper layer pyramidal neurons were permanently decreased, predominantly in female offspring, who also showed impaired somatosensory behavior. Molecular analyses of human postmortem brain specimens suggested similarities between mouse placental ALLO insufficiency and human preterm cortical development. Building on these published findings and on preliminary data showing that placental ALLO loss is associated with decreased cortical GABAergic interneuron density, altered GABA system-related gene expression, and changes in spontaneous inhibitory post-synaptic currents in mouse somatosensory cortex, we propose a new series of experiments in our mouse model to test the hypotheses that placental ALLO loss (1) disrupts the production and survival of specific cortical interneuron subclasses and (2) permanently alters the cortical excitation/inhibition (E/I) balance. We will then extend our analysis using our recently established in vitro brain organoid system to (3) define dosage and timing of ALLO exposure and withdrawal across multiple stages of human cortical interneuron development. Together, these next studies will elucidate new mechanisms by which placental hormones, including ALLO, can shape GABAergic cortical development. This work is starting to fundamentally change our understanding of developmental brain disorders and the placenta’s role in shaping long-term neurological outcomes and moves us closer to use of novel therapies based on placental hormones to prevent or ameliorate neurodevelopmental...