Mechanisms of Valproic Acid-Induced Neurodevelopmental and Behavioral Defects

描述(申请人提供)：怀孕早期神经系统的正常发育特别容易受到环境毒素和遗传遗传因素的影响，遗传因素可能导致出生后大脑连接错误。丙戊酸 酸(VPA)是一种抗癫痫和稳定情绪的药物，在怀孕期间服用会导致神经发育缺陷，如行为和认知功能障碍，包括自闭症谱系障碍和智力迟缓儿童的适应不良。影响的严重程度似乎取决于母亲接触的孕期。VPA是一种组蛋白脱乙酰酶抑制剂，提示它通过表观遗传机制干扰基因表达。我们观察到，妊娠早期给予VPA可增加脑源性神经营养因子(BDNF)的表达，BDNF是一种神经营养因子，在胎儿大脑中起着神经发生的关键调节因子的作用。 这导致了这一提议的工作假说：在胎儿大脑发育期间，VPA对BDNF表达的表观遗传刺激会导致前脑神经发生缺陷和行为缺陷。这一假说将通过确定1)VPA诱导的BDNF表达的刺激在多大程度上是通过特定BDNF基因启动子的DNA甲基化和/或共价组蛋白修饰来介导的；2)皮质锥体神经元和GABA能中间神经元的比例因胚胎暴露于VPA而发生变化的程度；以及3)通过TrkB受体改变的BDNF信号在介导VPA对胚胎前脑神经发生和认知的影响中的作用。这将利用一种带有突变的TrkB受体的新型转基因小鼠来完成，该受体被设计为通过注射外源拮抗剂来选择性和可逆地阻断。对于后一项实验的预测是，当BDNF信号通路被抑制时，VPA将无法诱导神经遗传学缺陷和异常行为。这项研究的目的是确定胎儿暴露于临床使用的药物VPA导致神经发育缺陷的机制。这将使我们能够确定有针对性的信号通路，以避免对需要VPA控制癫痫和双相情感障碍的孕妇产生不利的神经发育影响。此外，该项目寻求建立一个模型，使系统研究环境因素影响大脑发育的机制，以及环境和遗传因素如何相互作用导致自闭症和其他神经发育障碍。

DESCRIPTION (provided by applicant): The proper development of the nervous system during early pregnancy is particularly vulnerable to both environmental toxins and the effects of inherited genetic factors which can lead to errors in connectivity in the postnatal brain. Valproic acid (VPA) is an antiepileptic and mood stabilizing drug that, when administered during pregnancy, causes neurodevelopmental defects such as behavioral and cognitive dysfunction, including maladaptations observed in children with autism spectrum disorder and intellectual delay. The severity of effects appears to be dependent upon gestational time of maternal exposure. VPA is a histone deacetylase inhibitor, suggesting that it interferes with gene expression by an epigenetic mechanism. We have observed that administration of VPA to pregnant mice during early gestation increases the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that acts as a critical modulator of neurogenesis in the fetal brain. This has led to the working hypothesis for this proposal: epigenetic stimulation of BDNF expression by VPA during fetal brain development causes defective forebrain neurogenesis and behavioral deficits. This hypothesis will be tested by determining 1) the extent to which VPA-induced stimulation of BDNF expression is mediated by DNA methylation and/or covalent histone modification at specific BDNF gene promoters; 2) the extent to which the proportions of cortical pyramidal neurons and GABAergic interneurons are altered by embryonic exposure to VPA; and 3) the role of altered BDNF signaling, through the trkB receptor, in mediating the effects of VPA on embryonic forebrain neurogenesis and cognition. This will be accomplished utilizing a novel transgenic mouse with a mutant trkB receptor, engineered to be selectively and reversibly blocked by administration of an exogenous antagonist. The prediction for the latter experiments is that VPA will fail to induce neurogenetic defects and abnormal behavior when the BDNF signaling pathway is inhibited. The goal of this research is to determine the mechanism by which fetal exposure to a clinically used agent, VPA, induces neurodevelopmental defects. This would enable the identification of signaling pathways that can be targeted to avoid adverse neurodevelopmental effects in pregnant women who require VPA for control of epilepsy and bipolar disorder. In addition, the project seeks to establish a paradig that would enable systematic investigation of the mechanisms by which environmental agents affect brain development as well as how environmental and genetic factors might interact to cause autism and other neurodevelopmental disorders.