Novel Roles of Placental Allopregnanolone in Brain Development and Injury

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ABSTRACT Compromised placental function is highly associated with abnormal fetal development, especially of the brain. Abnormal brain development or fetal brain injury leads to life-long neurological impairments, including cerebral palsy, seizures and mental disabilities. Placental dysfunction may place many thousands of fetuses at risk of life-long impairments each year. The vast majority of research connecting placental compromise to fetal brain injury has focused on gas exchange or nutritional programming, neglecting the placenta's essential neuroendocrine role. Using new molecular models, we are testing our overall hypothesis that key placental hormones contribute to normal brain development and that their loss contributes to injury. One such critical placental hormone is allopregnanolone (ALLO), the most potent GABAergic neurosteroid derived from progesterone. In both rodent and human gestation, ALLO is made predominantly by the placenta. Our preliminary experiments have shown that pharmacological ALLO reduction during gestation disrupts cortico-hippocampal circuit maturation and alters GABAergic subunit expression. Additionally, endogenous and exogenous ALLO provides neuroprotection in multiple preclinical injury models. To use ALLO as a perinatal therapeutic agent, however, it is critical to understand the specific source, physiological levels and actions of ALLO in gestation. Until now, these investigations have been limited by lack of tools designed to precisely alter and measure placental neurosteroids, barriers we have overcome through generation of new mouse models and use of advanced mass spectroscopy. We have generated mouse models in which ALLO production is suppressed only in placenta. These models allow direct placental steroid manipulation for the first time. We have shown that suppression of placental ALLO production results in a specific reduction of proliferating intermediate progenitor cells (IPCs) in the cortical subventricular zone during gestation and that there are long-lasting functional neurological alterations after placental ALLO is suppressed. Using our new floxed mouse model (AKR1c14fl/fl) in which the gene for 3αHSD can be deleted in a tissue-specific manner, we will determine the extent to which placental ALLO is critical to: 1) corticogenesis; 2) long-term behavior and circuit function; and 3) injury that may be amenable to perinatal treatment. Elucidation of the mechanisms by which placental hormones, including ALLO, shape normal and abnormal cortical development would fundamentally change our understanding of developmental brain disorders and the placenta's role in shaping long-term neurological outcomes. These experiments also provide the possibility to prevent or ameliorate developmental brain injury through novel therapies based on placental hormones.