Elucidating Aberrant Dopamine Release in Schizophrenia

阐明精神分裂症中多巴胺的异常释放

• 批准号: 8055400
• 负责人: HUI ZHANG
• 金额: $ 19.92万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055400
• 关键词: 22q11; 22q11.2; A Mouse; Amphetamines; Animal Model; Antipsychotic Agents; Chromosome Deletion; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine Antagonists; Dose; Fluorescence; Human; Hyperactive behavior; Image; Individual; Lead; Measures; Mus; Neurotransmitters; Pathway interactions; Patients; Physiologic pulse; Prefrontal Cortex; Public Health; Reporter; Role; Scanning; Schizophrenia; Slice; Symptoms; Synaptic Vesicles; Testing; Training; Wild Type Mouse; density; dopamine system; dopamine transporter; high risk; insight; microdeletion; mouse model; mutant; nerve supply; neurotransmission; novel; novel strategies; optical imaging; presynaptic; public health relevance; response; transmission process; uptake

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating disease of major public health importance. Although the causes of schizophrenia are not known, a role for hyperactivity of the dopamine system in the positive symptoms associated with schizophrenia has long been inferred from the antipsychotic response to D2 dopamine receptor antagonists and because the dopamine releaser amphetamine can be psychotogenic. Recent imaging studies suggest enhanced amphetamine induced dopamine release in schizophrenia patients but the underlying mechanisms are unknown, in part due to the lack of an animal model. Individuals with 22q11.2 microdeletion have cognitive deficits and a high risk of developing schizophrenia. A mouse model carrying a 1.3-Mb chromosomal deletion, Df(16)A mice, that is synthetic to the human 22q11.2 1.5-Mb microdeletion shows features that parallel schizophrenia. Our preliminary data indicate that there is an altered dopamine release in acutely derived corticostriatal slices. We hypothesize that dopamine dysregulation in schizophrenia is in part due to intrinsic changes in the presynaptic dopamine terminals. To test this hypothesis, we propose to characterize dopamine storage, release, and plasticity in this mouse model both in the striatum and prefrontal cortex. We will employ fast-scan cyclic voltammetry and a novel optical imaging approach which enables to visualize dopamine storage and release at individual terminals to elucidate the mechanisms that may underlie the aberrant dopamine release in schizophrenia. In particular, we plan to determine whether dopamine transporters and/or the synaptic vesicle pH have been altered in the mutants. These studies will reveal the mechanisms underlying the dysregulation of dopamine neurotransmission and may offer insights into the development of new approaches for the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: We propose to characterize dopamine release in a mouse model of schizophrenia, the 22q11.2 microdeletion mice, to test the hypothesis that dopamine dysregulation in schizophrenia in part results from intrinsic changes in the presynaptic dopamine terminals.

描述（由申请人提供）：精神分裂症是一种具有重大公共卫生重要性的使人衰弱的疾病。虽然精神分裂症的病因尚不清楚，但长期以来，人们从 D2 多巴胺受体拮抗剂的抗精神病反应中推断出多巴胺系统过度活跃在精神分裂症相关阳性症状中的作用，并且因为多巴胺释放剂安非他明可能具有致精神病性。最近的影像学研究表明，安非他明诱导精神分裂症患者多巴胺释放增强，但其潜在机制尚不清楚，部分原因是缺乏动物模型。 22q11.2 微缺失的个体存在认知缺陷，并且患精神分裂症的风险很高。携带 1.3 Mb 染色体缺失的小鼠模型 Df(16)A 小鼠是与人类 22q11.2 1.5 Mb 微缺失合成的，显示出与精神分裂症相似的特征。我们的初步数据表明，急性衍生的皮质纹状体切片中的多巴胺释放发生了改变。我们假设精神分裂症中的多巴胺失调部分是由于突触前多巴胺末端的内在变化。为了检验这一假设，我们建议表征该小鼠模型中纹状体和前额皮质的多巴胺储存、释放和可塑性。我们将采用快速扫描循环伏安法和一种新颖的光学成像方法，该方法能够可视化各个终端的多巴胺储存和释放，以阐明精神分裂症中多巴胺异常释放的机制。特别是，我们计划确定突变体中多巴胺转运蛋白和/或突触小泡 pH 值是否发生了改变。这些研究将揭示多巴胺神经传递失调的机制，并可能为精神分裂症治疗新方法的开发提供见解。 公共健康相关性：我们建议描述精神分裂症小鼠模型（22q11.2 微缺失小鼠）中多巴胺释放的特征，以检验精神分裂症中多巴胺失调部分由突触前多巴胺末端的内在变化引起的假设。