Elucidating Aberrant Dopamine Release in Schizophrenia

阐明精神分裂症中多巴胺的异常释放

基本信息

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
项目类别：
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

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

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项目摘要

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（申请人提供）：精神分裂症是一种使公共健康重要性的令人衰弱的疾病。尽管尚不清楚精神分裂症的原因，但多巴胺系统在与精神分裂症相关的阳性症状中的过度活跃性的作用长期以来一直是从对D2多巴胺受体拮抗剂的抗精神病药反应中推断出来的，并且由于多巴胺释放蛋白酶释放蛋白酶释链胺可以是精神上的。最近的成像研究表明，精神分裂症患者中苯丙胺诱导的多巴胺释放增强，但潜在的机制尚不清楚，部分原因是缺乏动物模型。具有22q11.2微骨骼的个体具有认知缺陷，并且患有精神分裂症的高风险。携带1.3-MB染色体缺失的小鼠模型DF（16）A小鼠，该模型与人22q11.2 1.5-Mb微骨骼合成，显示出与精神分裂症平行的特征。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变化。我们假设精神分裂症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，我们建议在纹状体和额叶皮层中的该小鼠模型中表征多巴胺的储存，释放和可塑性。我们将采用快速扫描的环状伏安法和一种新型的光学成像方法，使我们能够可视化多巴胺的存储并在单个末端释放，以阐明可能是精神分裂症中异常多巴胺释放的机制。特别是，我们计划确定多巴胺转运蛋白和/或突触囊泡pH是否已在突变体中改变。这些研究将揭示多巴胺神经传递失调的基础机制，并可能会提供有关开发精神分裂症治疗新方法的见解。公共卫生相关性：我们建议在精神分裂症的小鼠模型22q11.2微骨骼小鼠中表征多巴胺释放，以检验以下假说，即精神分裂症的多巴胺失调部分是由于偏红色多巴胺末端的内在变化所致。