Sex-specific development of seizure activity following endocannabinoid system manipulation in the fetal brain

项目摘要 先兆子痫是一种妊娠期高血压疾病，当母亲 出现了新的癫痫发作导致一些先兆子痫患者进展到 子痫是未知的。长期目标是确定治疗靶点， 妊娠期癫痫和先兆子痫，并追求作为一个学术科学家的职业生涯。的 本申请的总体目标是：1）鉴定内源性大麻素系统是否 参与临床前子痫模型中癫痫发作敏感性的增加，以及2）为我提供 额外的培训，以建立一个成功的职业生涯作为一个学术科学家。中央 假设大麻素受体1（CB 1 R）活性的变化在大麻素受体1（CB 1 R）活性降低后受损， 子宫胎盘灌注（RUPP）和受损的CB 1 R激活增加癫痫发作的严重程度。 该项目的基本原理是，大鼠RUPP模型显示出增加的癫痫易感性; 然而，促成因素尚不完全清楚。此外，癫痫发作发生时，大脑 活性没有被有效地调节，并且已经显示内源性大麻素系统调节 神经元活动，并在癫痫发作活动中发挥重要作用。我们的初步工作表明 小鼠内源性大麻素系统活性重要酶的异常表达 RUPP模型由于这些酶在调节CB 1 R活性中起重要作用，因此， RUPP可能干扰内源性大麻素系统调节神经元的能力， 活动，从而增加对癫痫发作的敏感性。目标1将决定RUPP是否损害 CB 1 R活性以及调节CB 1 R活性是否会增加RUPP后癫痫发作的严重程度。 我在Aim 2中的博士后计划专注于后代，并将确定是否破坏 怀孕期间内源性大麻素系统导致癫痫的性别特异性差异， 青春期的后代这种应用是创新的，因为它结合了临床相关的 用一种成熟的神经元调节剂，内源性大麻素， 因此具有鉴定新的治疗靶点的潜力。这笔赠款还将允许 持续的职业发展和成功的一个非常有前途的神经科学家。

Project Summary Preeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia, when the mother displays novel seizures. The mechanisms that cause some preeclampsia patients to advance to eclampsia are unknown. The long-term goals are to identify therapeutic targets to prevent seizures in pregnancy and preeclampsia and to pursue a career as an academic scientist. The overall objectives of this application are to: 1) identify whether the endocannabinoid system is involved in increased seizure sensitivity in preclinical model of eclampsia, and 2) provide me the additional training to establish a successful career as an academic scientist. The central hypothesis is that changes in cannabinoid receptor 1 (CB1R) activity is impaired following reduced utero-placental perfusion (RUPP) and that impaired CB1R activation increases seizure severity. The rationale for this project is that the rat RUPP model showed increased seizure susceptibility; however, the contributing factors are not fully known. Additionally, seizures occur when brain activity is not effectively modulated and the endocannabinoid system has been shown to modulate neuronal activity and play a significant role in seizure activity. Our preliminary work shows abnormal expression of enzymes important for endocannabinoid system activity in a mouse RUPP model. Because these enzymes play an important role in modulating CB1R activity, it is possible that the RUPP interferes with the endocannabinoid system’s ability to modulate neuronal activity and thus increases sensitivity to seizures. Aim 1 will determine whether RUPP impairs CB1R activity and whether modulating CB1R activity increases seizure severity following RUPP. My postdoctoral plans in Aim 2 focus on the offspring and will determine whether disrupting the endocannabinoid system during pregnancy leads to sex-specific differences in epilepsy in the adolescent offspring. This application is innovative because it combines a clinically-relevant preclinical model of eclampsia with a well-established neuronal modulator, the endocannabinoids, thus having the potential to identify a novel therapeutic target. This grant will also allow for the continued career development and success of a very promising neuroscientist.