Mechanisms of Valproic Acid-Induced Neurodevelopmental and Behavioral Defects

丙戊酸诱发神经发育和行为缺陷的机制

基本信息

批准号：
8812895
负责人：
BRUCE K KRUEGER
金额：
$ 31.05万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812895
关键词：
Affect Antiepileptic Agents Autistic Disorder Behavior Behavior Disorders Behavioral Bipolar Disorder Brain Brain-Derived Neurotrophic Factor Cerebral cortex Child Cognition Cognition Disorders Cognitive deficits DNA Methylation Defect Development Embryo Engineering Epigenetic Process Epilepsy Exposure to Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Goals Growth Histone Deacetylase Inhibitor Impaired cognition Incidence Inherited Interneurons Investigation Knock-in Mouse Lead Literature Longevity Maternal Exposure Medial Mediating Molecular Target Moods Mothers Mus Mutate Neurodevelopmental Disorder Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Perinatal Exposure Pharmaceutical Preparations Predisposition Pregnancy Pregnant Women Production Prosencephalon Relative (related person)Reporting Research Rodent Role Severities Signal Pathway Signal Transduction Testing Therapeutic Time Toxic Environmental Substances Transgenic Mice Tyrosine Kinase Inhibitor Valproic Acid Ventricular Woman Work autism spectrum disorder base environmental agent epigenetic regulation excitatory neuron fetal hippocampal pyramidal neuron histone modification in utero in vivo inhibitory neuron migration mutant nervous system development neurogenesis neurogenetics neurotrophic factor novel offspring postnatal pregnant prenatal exposure promoter research study

项目摘要

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.

描述（由申请人提供）：怀孕初期神经系统的适当发展尤其容易受到环境毒素的影响，以及遗传因素的影响，这可能导致产后大脑的连通性错误。门务酸（VPA）是一种抗癫痫药和情绪稳定药物，在怀孕期间给药时会导致神经发育缺陷，例如行为和认知功能障碍，包括在自闭症谱系障碍和智力延迟儿童中观察到的不适。影响的严重程度似乎取决于孕产妇暴露的妊娠时间。 VPA是一种组蛋白脱乙酰基酶抑制剂，表明它通过表观遗传机制干扰基因表达。我们已经观察到，早期妊娠期间对怀孕小鼠的施用会增加脑衍生的神经营养因子（BDNF）的表达，这是一种神经营养蛋白，是胎儿脑中神经发生的关键调节剂。这导致了该建议的工作假设：VPA在胎儿脑发育过程中对BDNF表达的表观遗传刺激会导致前脑神经发生和行为缺陷。该假设将通过确定1）在特定BDNF基因启动子上通过DNA甲基化和/或共价组蛋白修饰介导VPA诱导的BDNF表达刺激的程度； 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而改变； 3）通过TRKB受体改变BDNF信号传导的作用，介导VPA对胚胎前脑神经发生和认知的影响。这将通过使用一种突变的TRKB受体的新型转基因小鼠来实现，该小鼠通过施用外源性拮抗剂进行选择性和可逆地阻止。后一个实验的预测是，当抑制BDNF信号通路时，VPA将无法诱导神经遗传缺陷和异常行为。这项研究的目的是确定胎儿暴露于临床使用的药物VPA的机制，从而诱导神经发育缺陷。这将使可以识别可以针对的信号通路，以避免需要VPA控制癫痫和双相情感障碍的孕妇的不良神经发育影响。此外，该项目试图建立一个范式，该范式将对环境药物影响大脑发育以及环境因素和遗传因素如何相互作用以引起自闭症和其他神经发育障碍的机制进行系统的研究。