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Gene X Environment Interactions in Synaptic Plasticity of Neural Systems

神经系统突触可塑性中的基因 X 环境相互作用

基本信息

批准号：
8071146
负责人：
MICHAEL COLIN WILSON
金额：
$ 21.93万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071146
关键词：
Address Adopted Affect Agonist Alleles Animal Model Attention Attention deficit hyperactivity disorder Automobile Driving Behavior Biochemical Biological Assay Brain Candidate Disease Gene Child Clinical Cognitive Cognitive deficits Coloboma Complex Corpus striatum structure Coupled Data Development Disease Dopamine D2 Receptor Dopamine Receptor Down-Regulation Electrophysiology (science)Elements Employee Strikes Environment Environmental Exposure Environmental Impact Environmental Risk Factor Epigenetic Process Excision Exposure to Funding Future G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Genetic Glutamates Goals Heritability Heterozygote Human Immunohistochemistry Incidence Individual Inheritance Patterns Interneurons Investigation Laboratories Lead Lesion Life Ligand Binding Long-Term Depression Mediating Mental disorders Midbrain structure Modeling Molecular Genetics Mus Mutant Strains Mice Mutation Neural Pathways Neurons Neuropharmacology Nicotine Output Pathology Pathway interactions Play Population Predisposition Prevalence Process Proteins Receptor Signaling Regulation Research Risk Factors Role S-nitro-N-acetylpenicillamine SNAP receptor Schizophrenia School-Age Population Short-Term Memory Siblings Signal Transduction Sum Susceptibility Gene Synapses Synaptic Transmission Synaptic plasticity System Testing Transgenic Organisms Variant Wild Type Mouse base cholinergic desensitization endophenotype environmental stressor executive function fetal tobacco exposure genetic linkage innovation maternal cigarette smoking mouse model mutant neural circuit neurochemistry neurophysiology neuropsychiatry neurotransmitter release population based preclinical study prenatal prenatal exposure presynaptic public health relevance receptor expression relating to nervous system research study synaptosomal-associated protein 25 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): There is considerable evidence that the interaction between genetic susceptibly and environmental (GxE) risk factors plays a significant role in neuropsychiatric disease. In particular, GxE interactions are exemplified by attention-deficit hyperactivity disorder (ADHD) and schizophrenia that are prominent heterogeneous mental illnesses, with ADHD affecting 5-8% of school-aged children and schizophrenia having a life-long prevalence of 0.5-1%. While several genetic loci have been implicated in the heritability of these disorders, and environmental factors have been identified from population-based studies, there are few animal models that have been developed to examine the impact of GxE effects to study the mechanism of these interactions. In this application, we address this important goal by exploiting the hypothesis that the convergence of genetically encoded deficits in SNAP-25 expression, resulting selective deficiencies in synaptic transmission, and the environmental impact of prenatal nicotine exposure during brain development leads to emergent alterations of synaptic plasticity in the striatum. The potential involvement of the neural SNARE protein SNAP-25 as a candidate gene for neuropsychiatric disease has been revealed in our early studies of the hyperactive mouse mutant coloboma, more recently by genetic linkage studies in the ADHD population and by number of biochemical analyses schizophrenia. Similarly, maternal smoking is associated with increased incidence of ADHD. Towards this goal, we propose two Specific Aims in an R21 proposal that we believe may have high impact in the field by developing this model of GxE that can be evaluated mechanistically by targeting the genetic lesion to different neural systems and by receptor signaling assays that are contribute to synaptic plasticity in the striatum. Our strategy is to develop an innovative, integrated approach that capitalizes on the molecular genetic, neuropharmacological and electrophysiological expertise of our laboratories. The Specific Aims are: 1) to evaluate mechanism of GxE effects on synaptic plasticity (long-term depression, LTD) through dopamine D2 receptor signaling and expression and 2) to identify those components of striatal circuitry responsible for deficits in synaptic plasticity by targeting haploinsufficiency of the Snap25 gene to specific inputs to the striatum. Ultimately, we expect that this strategy could be adopted and expanded to define the significant contributions of GxE factors to alterations in gene expression and epigenetic regulation, and the deficits in synaptic plasticity and cognitive behaviors that are the cornerstones of mental illness. Furthermore we believe that this research will aid in the development of better, more targeted therapeutics tuned at a systems level to the neurophysiological basis of neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Many prominent neuropsychiatric disorders, such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia, show a clear pattern of inheritance, as well as a striking role for environmental risk factors. Despite this clear evidence for the role of genes x environment interactions, the lack of well-defined animal models has limited our ability to understand the fundamental basis of how these factors interact to promote different clinical presentations of neuropsychiatric disease. Our investigation of a mouse model based on SNAP25 as susceptibility gene and prenatal nicotine exposure would not only help resolve the neurophysiological mechanisms involved, but importantly should aid in the development of better targeted therapeutics based on the brain circuitry revealed by these studies.

描述(由申请人提供)：有相当多的证据表明，遗传易感性和环境(GxE)风险因素之间的相互作用在神经精神疾病中发挥着重要作用。特别是，GxE相互作用的例子是注意力缺陷多动障碍(ADHD)和精神分裂症，这是一种突出的异质性精神疾病，ADHD影响5-8%的学龄儿童，精神分裂症的终生患病率为0.5-1%。虽然已有几个遗传位点与这些疾病的遗传性有关，环境因素也已从基于人群的研究中确定，但很少有动物模型被开发来检查GxE效应的影响，以研究这些相互作用的机制。在这一应用中，我们通过利用以下假设来解决这一重要目标：SNAP-25表达的遗传编码缺陷的收敛，导致突触传递的选择性缺陷，以及大脑发育期间产前尼古丁暴露的环境影响导致纹状体突触可塑性的紧急变化。神经陷阱蛋白SNAP-25作为神经精神疾病候选基因的潜在参与已经在我们对过度活跃的小鼠突变缺陷体的早期研究中揭示，最近通过在ADHD人群中的遗传连锁研究和一些生化分析精神分裂症。同样，母亲吸烟与ADHD发病率的增加有关。为了实现这一目标，我们在R21提案中提出了两个特定的目标，我们认为通过开发这个GxE模型可能在该领域产生很高的影响，该模型可以通过将遗传损伤靶向不同的神经系统和通过有助于纹状体突触可塑性的受体信号分析来进行机械评估。我们的战略是开发一种创新的综合方法，利用我们实验室的分子遗传学、神经药理学和电生理学专业知识。其具体目的是：1)通过多巴胺D2受体的信号和表达，评估GxE对突触可塑性(LTD)的影响机制；2)通过靶向Snap25基因对纹状体特定输入的单倍性不足，识别导致突触可塑性缺陷的纹状体回路成分。最终，我们预计这一策略可以被采用和扩展，以确定GxE因子对基因表达和表观遗传调控的重大贡献，以及突触可塑性和认知行为的缺陷，这些都是精神疾病的基石。此外，我们相信这项研究将有助于开发更好的、更有针对性的治疗方法，在系统水平上调整到神经精神障碍的神经生理学基础。公共卫生相关性：许多突出的神经精神疾病，如注意力缺陷多动障碍(ADHD)和精神分裂症，都显示出明显的遗传模式，以及环境风险因素的显著作用。尽管有关于基因和环境相互作用的明确证据，但缺乏明确定义的动物模型限制了我们理解这些因素如何相互作用以促进神经精神疾病不同临床表现的基本基础的能力。我们对以SNAP25为易感基因的小鼠模型和产前尼古丁暴露的研究不仅有助于解决相关的神经生理机制，而且重要的是应该有助于基于这些研究揭示的大脑回路开发更好的靶向疗法。