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: 8610335
• 负责人: BRUCE K KRUEGER
• 金额: $ 30.96万
• 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/8610335
• 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因素的影响，这可能导致出生后大脑连接错误。丙戊酸 酸（VPA）是一种抗癫痫和情绪稳定药物，在怀孕期间服用会导致神经发育缺陷，例如行为和认知功能障碍，包括在患有自闭症谱系障碍和智力迟缓的儿童中观察到的适应不良。影响的严重程度似乎取决于母亲接触该物质的妊娠时间。 VPA 是一种组蛋白脱乙酰酶抑制剂，表明它通过表观遗传机制干扰基因表达。我们观察到，在妊娠早期给怀孕小鼠注射 VPA 会增加脑源性神经营养因子 (BDNF) 的表达，脑源性神经营养因子是一种神经营养蛋白，在胎儿大脑中充当神经发生的关键调节剂。 这引出了该提案的工作假设：胎儿大脑发育过程中 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。 该假设将通过以下确定进行检验：1) VPA 诱导的 BDNF 表达刺激是由特定 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 信号传导在介导 VPA 对胚胎前脑神经发生和认知的影响中的作用。这将利用具有突变 trkB 受体的新型转基因小鼠来实现，该受体被设计为通过施用外源拮抗剂来选择性和可逆地阻断。后面实验的预测是，当 BDNF 信号通路受到抑制时，VPA 将无法诱发神经遗传缺陷和异常行为。 本研究的目的是确定胎儿接触临床使用的药物 VPA 诱发神经发育缺陷的机制。这将有助于识别信号通路，从而避免对需要 VPA 来控制癫痫和双相情感障碍的孕妇产生不良神经发育影响。此外，该项目还试图建立一个范式，能够系统地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。