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

• 批准号: 8431364
• 负责人: BRUCE K KRUEGER
• 金额: $ 30.23万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431364
• 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; Regulation; 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; 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

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）：妊娠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，这可能导致出生后大脑连接错误。丙 VPA是一种抗癫痫和情绪稳定药物，当在怀孕期间施用时，会导致神经发育缺陷，如行为和认知功能障碍，包括在自闭症谱系障碍和智力发育迟缓儿童中观察到的适应不良。影响的严重程度似乎取决于母体接触的妊娠时间。VPA是一种组蛋白脱乙酰酶抑制剂，表明其通过表观遗传机制干扰基因表达。我们已经观察到，在妊娠早期对妊娠小鼠给予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，是胎脑神经发生的关键调节因子。 这导致了这项提议的工作假设：在胎儿大脑发育期间VPA对BDNF表达的表观遗传刺激导致前脑神经发生缺陷和行为缺陷。 该假设将通过确定1）VPA诱导的BDNF表达的刺激由特定BDNF基因启动子处的DNA甲基化和/或共价组蛋白修饰介导的程度; 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而改变的程度; 3）通过trkB受体改变BDNF信号在VPA对胚胎前脑神经发生和认知的影响中的作用。这将利用具有突变型trkB受体的新型转基因小鼠来实现，所述突变型trkB受体经工程改造以通过施用外源性拮抗剂而被选择性地和可逆地阻断。对后一实验的预测是，当BDNF信号通路被抑制时，VPA将不能诱导神经遗传缺陷和异常行为。 本研究的目的是确定胎儿暴露于临床使用的药物VPA诱导神经发育缺陷的机制。这将有助于识别信号通路，这些信号通路可以有针对性地避免需要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，该项目旨在建立一个paradig，以便系统地调查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。