Gene-environment interactions in a novel schizophrenia model using DISC1 and Reelin gene mutations

使用 DISC1 和 Reelin 基因突变的新型精神分裂症模型中的基因-环境相互作用

• 批准号: 9610563
• 负责人: Heather Mahoney
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-14 至 2020-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9610563
• 关键词: Acids; Adult; Affect; Anatomy; Anhedonia; Animal Model; Area; Behavior; Behavioral; Biology; Cell physiology; Cell surface; Cognition; Cognitive deficits; Complement; DISC1 gene; DNA Sequence Alteration; Data; Development; Developmental Course; Disease; Disinhibition; Dominant-Negative Mutation; Economic Burden; Electrophysiology (science); Environmental Risk Factor; Etiology; Exposure to; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Glutamates; Goals; Hippocampus (Brain); Histocompatibility; Human; Immune; Individual; Knowledge; Lead; Learning; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Microglia; Modeling; Molecular; Morphology; Motor Activity; Mus; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; Neurobehavioral Manifestations; Neurobiology; Neuroimmune; Neurons; Neurotransmitter Receptor; Neurotransmitters; Pathology; Pathway interactions; Patients; Phenotype; Population; Predisposition; Prefrontal Cortex; Prophylactic treatment; Psychotic Disorders; Regulation; Research; Risk; Risk Factors; Schizophrenia; Short-Term Memory; Signal Pathway; Susceptibility Gene; Symptoms; Synapses; Synaptic plasticity; System; Variant; Viral; adult neurogenesis; base; complement pathway; drug discovery; effective therapy; endophenotype; gene environment interaction; genetic association; genetic risk factor; glutamatergic signaling; immune activation; improved; migration; mimetics; mouse model; neurogenesis; new therapeutic target; newborn neuron; novel; prenatal; receptor expression; response; sensory gating; spatial memory; symptom treatment; synergism; therapeutic development; treatment strategy

The goal of this project is to investigate the phenotype of a novel mouse model of schizophrenia (SCZ). Many genetic models of SCZ have been proposed, however, drug discovery has been limited and focused on treating symptoms of psychosis. We propose to evaluate a novel gene x environment interaction model of SCZ, and identify the common pathways contributing to disease development as novel targets for the development of therapeutics or prophylaxis. The glutamate pathway is a key contributor to the symptoms of SCZ, and our model represents multiple hits, genetic and environmental, to this pathway. We will subject mice with mutations in the Disrupted-in-Schizophrenia (DISC1) and Reelin (RELN) genes to prenatal immune activation using the viral mimetic Polyriboinosinic:polyribocytidylic acid (Poly I:C), and evaluate SCZ-like pathology and behavior. This is a highly salient model for SCZ, incorporating two distinct genetic mutations that are: 1) associated with SCZ; 2) produce similar neurobiological alterations; and 3) interact with immune activation to produce SCZ-relevant behavioral changes. Immune activation, while not a new area of study in relation to SCZ, has recently come under the spotlight with genetic susceptibility studies pinpointing complement component 4 (C4) genes as an important point of association between SCZ and variations in the major histocompatibility locus, and we expect this immune activation to exacerbate our SCZ phenotypes. This project bridges multiple SCZ hypotheses in a much needed integrative approach. We hypothesize that combined disruption of DISC1 and RELN will result in a more severe SCZ-like phenotype than either mutation alone, including behavioral and learning deficits, altered neurogenesis and dendritic morphology, and changes in complement pathway molecule expression; and these changes will be exacerbated by prenatal immune activation. Aim 1 will characterize the behavioral endophenotype of mice expressing dominant negative truncated human DISC1, and 50% of the normal amount of reelin, as it relates to expected SCZ behavior. Our preliminary data indicates changes in affect and cognition. Aim 2 will evaluate behavior with the addition of an environmental insult, prenatal immune activation, that is known to produce SCZ-like behavior, and to interact with both mutations individually. Aim 3 will determine if there are changes in complement molecule expression, neurogenesis, and long-term potentiation following both genetic and environmental hits. As this is the first study to characterize this model of SCZ, positive or negative data will add to the body of knowledge about the underlying biology of SCZ.

本项目的目标是研究一种新的精神分裂症小鼠模型(SCZ)的表型。 许多SCZ的遗传模型已经被提出，然而，药物的发现一直是有限的，并且集中在 治疗精神病的症状。我们建议评估一个新的基因x环境互作模型。 SCZ，并确定促进疾病发展的共同途径，作为新的目标 治疗或预防的发展。谷氨酸途径是引起糖尿病症状的关键因素。 SCZ，而我们的模型代表了这一途径的多个命中，遗传和环境。我们会让小白鼠 精神分裂症(DISC1)和Reelin(RELN)基因突变与产前免疫 使用病毒模拟物多聚核苷：多核胞苷酸(Poly I：C)激活，并评估SCZ-like 病理学和行为。这是SCZ的一个非常显著的模型，结合了两个不同的基因突变 是：1)与SCZ有关；2)产生类似的神经生物学改变；以及3)与免疫相互作用 激活以产生与SCZ相关的行为变化。免疫激活，虽然不是一个新的研究领域 与SCZ的关系最近受到了人们的关注，遗传易感性研究准确地指出了 补体成分4(C4)基因作为SCZ与遗传性疾病变异之间的一个重要关联点 主要的组织相容性基因座，我们预计这种免疫激活会加剧我们的SCZ表型。这 该项目以一种迫切需要的综合方法连接了多个SCZ假设。我们假设 DISC1和RELN的联合破坏将导致比任一突变更严重的SCZ样表型 单独，包括行为和学习障碍，改变的神经发生和树突形态，以及改变 补体途径分子的表达；而这些变化将因产前免疫而加剧 激活。目的1将表征显性阴性的小鼠的行为内表型 截短的人类DISC1，以及正常卷绕量的50%，因为它与预期的SCZ行为有关。我们的 初步数据表明，情感和认知发生了变化。目标2将通过添加一个 环境伤害，产前免疫激活，已知会产生类似SCZ的行为，并相互作用 两个突变都是单独存在的。目标3将确定补体分子表达是否发生变化， 神经发生，以及遗传和环境打击后的长期增强。因为这是第一次 研究这一SCZ模型的特征，正数据或负数据将增加关于 SCZ的潜在生物学。