Placental Allopregnanolone is Essential for Development of Cortical GABAergic Signaling

项目摘要 早产（PTB），发生在所有出生的10%，是高度相关的负面神经系统的结果， 自闭症精神分裂症和其他精神疾病在所有PTB中，胎盘过早丢失， 可能会产生潜在的有害后果。胎盘是健康妊娠的重要组成部分， 为发育中的胎儿提供胎儿尚未产生的必需激素，包括神经类固醇 别孕烯醇酮（ALLO）。因此，PTB引起的胎盘丢失可能导致神经发育中断， 一部分是由于关键的胎盘激素的丢失。ALLO水平在怀孕期间在母亲和胎儿中达到峰值， 胎盘合成由于ALLO可以作为GABAA受体（GABAA-1）的有效的正变构调节剂， R），同时调节其表达，胎盘ALLO暴露可调节胎儿GABA能 系统.在发育过程中，这些GABA能突触是第一个发挥功能的，它们的兴奋性突触是第一个发挥功能的。 作用促进依赖于活性的神经元成熟和整合。为了研究ALLO对早期 GABA能信号传导，我们创建了胎盘ALLO丢失的模型-Akrlc 14 Cyp 19 aKO小鼠（plKO）。这 模型具有独特的组织和激素特异性，使其成为检验假设的理想系统：胎盘 ALLO缺失破坏胎儿躯体感觉皮层中GABA能系统的发育， 这些后果会持续到成年。plKO的躯体感觉皮层的初步结果显示， 这些小鼠表现出躯体感觉功能的神经行为缺陷 类似于人类早产儿中的那些。plKO显示改变的抑制性突触后电流 （IPSC）在成熟的躯体感觉皮层，以及早期中断GABAA-R亚基和氯 离子转运蛋白KCC 2，调节GABA的兴奋-抑制转换。重要的是，其中许多 差异似乎是依赖于性别的。总之，文献和我们的数据表明， ALLO和GABA能信号可能是性别特异性的，但中断的时间和程度尚不清楚。 为了确定胎盘ALLO在GABA能信号传导中的具体作用，我将研究 以下目的：1）从分子上表征胎盘ALLO缺失对GABA能信号传导的影响， 发育中的皮质;和2）生理学上确定胎盘ALLO损失对胎儿发育的性别特异性后果。 新生儿大脑皮层的神经活动通过成功地完成这些目标，我将获得优秀的 在学术和实验室培训全面的假设检验，我将获得批判性分析技能 这是我为从事神经科学研究做准备的必要条件。

PROJECT SUMMARY Preterm birth (PTB), occurring in 10% of all births, is highly correlated with negative neurologic outcomes such as autism, schizophrenia, and other psychiatric disorders. In all PTBs, the placenta is lost prematurely, which may have potentially harmful consequences. The placenta is a critical component of healthy pregnancy that supplies the developing fetus with essential hormones not yet made by the fetus, including the neurosteroid Allopregnanolone (ALLO). Thus, placental loss due to PTB may contribute to disrupted neurodevelopment, in part through loss of critical placental hormones. ALLO levels peak in mother and fetus during pregnancy due to placental synthesis. Since ALLO can act as a potent, positive allosteric modulator of GABAA receptors (GABAA- R) and simultaneously regulate their expression, placental ALLO exposure may modulate fetal GABAergic systems. During development, these GABAergic synapses are the first to become functional and their excitatory actions facilitate activity depended neuronal maturation and integration. To investigate ALLO's effects on early GABAergic signaling, we created a model of placental ALLO loss - the Akr1c14Cyp19aKO mouse (plKO). This model is uniquely tissue and hormone specific, making it the ideal system to test the hypothesis: placental ALLO loss disrupts the development of the GABAergic systems in the fetal somatosensory cortex with consequences that persist into adulthood. Preliminary results from the somatosensory cortex of plKOs reveal decreases in upper-layer neurons and these mice exhibit neurobehavioral deficits in somatosensory function that resemble those seen in human preterm survivors. plKOs display altered inhibitory postsynaptic currents (IPSCs) in the mature somatosensory cortex, as well as early disruptions to GABAA-R subunits and the chloride ion transporter KCC2, that regulates the excitatory-to-inhibitory switch of GABA. Importantly, many of these differences appear to be sex-dependent. Collectively, the literature and our data indicate an interaction between ALLO and GABAergic signaling that may be sex-specific, but the timing and extent of the disruption is unknown. To determine the specific role of placental ALLO on the development of GABAergic signaling, I will investigate the following aims: 1) Molecularly characterize the effect of placental ALLO loss on GABAergic signaling in the developing cortex; and 2) physiologically determine the sex-specific consequences of placental ALLO loss on neural activity in the neonatal cortex. Through successful completion of these aims, I will receive outstanding academic and laboratory training in comprehensive hypothesis testing and I will acquire critical analysis skills that are essential as I prepare for a career in neuroscience research.