Novel Roles of Placental Allopregnanolone in Brain Development and Injury

摘要 胎盘功能受损与胎儿大脑发育异常高度相关，后来又与 神经发育障碍，如自闭症、癫痫和精神分裂症，但其原因机制 在很大程度上仍然不为人知。这些神经发育障碍的患病率在出生时就会增加。 早产或怀孕后出生，有证据表明胎盘功能不佳。皮质GABA能信号的改变 与许多神经发育障碍有关，但直到最近，检查 胎盘功能障碍、皮质发育改变与GABA能信号转导的关系 不存在。在这项计划的最初资助期，我们验证并使用了我们的新鼠标模型来 首次直接证明需要一种关键的胎盘激素--别孕酮(Allo) 对于正常的大脑发育来说，它的丢失会导致长期的神经功能障碍。阿洛是一个 强效GABA能神经类固醇，来源于孕酮，主要由胎盘合成。 啮齿动物和人类妊娠晚期导致胎盘来源的胎脑高浓度 你好。仅从胎盘中删除编码Allo合成酶的基因会导致 孕期等位基因暴露和产生的全球性、但与性别相关的和地区特有的变化 神经解剖学和行为学。胎盘同种异体生成量减少损害产前躯体感觉 皮质生成和上层锥体神经元永久性减少，主要发生在女性 后代，他们也表现出躯体感觉行为受损。人体尸检的分子分析 脑组织标本显示小鼠胎盘功能不全与人类早产相似 皮质发育。根据这些已发表的发现和初步数据显示，胎盘 等位基因丢失与皮质GABA能中间神经元密度降低、GABA系统相关改变有关 小鼠躯体感觉皮层自发抑制性突触后电流的基因表达和变化， 我们建议在我们的小鼠模型上进行一系列新的实验，以检验胎盘易位的假说 丢失(1)扰乱特定皮质中间神经元亚类的产生和存活，以及(2)永久性 改变大脑皮层兴奋/抑制(E/I)平衡。然后，我们将使用我们最近的 建立体外脑器官系统(3)确定异丙酚暴露和戒断的剂量和时机 在人类皮质间神经元发育的多个阶段。总之，这些下一步的研究将 阐明包括Allo在内的胎盘激素塑造GABA能皮质的新机制 发展。这项工作开始从根本上改变我们对发育性大脑障碍的理解 胎盘在塑造长期神经结果中的作用，并使我们更接近使用新的 以胎盘激素为基础的预防或改善神经发育障碍的治疗。

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 impairments.