Elucidating Aberrant Dopamine Release in Schizophrenia

描述(由申请人提供)：精神分裂症是一种对公共卫生具有重大意义的衰弱疾病。尽管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以及多巴胺释放剂苯丙胺可能是精神起因的角度，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。最近的成像研究表明，安非他明增强了精神分裂症患者的多巴胺释放，但其潜在机制尚不清楚，部分原因是缺乏动物模型。22q11.2微缺失的个体有认知缺陷，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，是由人类22q11.2 1.5-Mb微缺失合成的，显示出类似精神分裂症的特征。我们的初步数据表明，在急性派生的皮质纹状体切片中存在多巴胺释放的变化。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终末的内在变化。为了验证这一假设，我们建议在这个小鼠模型中表征纹状体和前额叶皮质中多巴胺的储存、释放和可塑性。我们将使用快速扫描循环伏安法和一种新的光学成像方法，能够可视化个别终端的多巴胺储存和释放，以阐明精神分裂症患者多巴胺异常释放的机制。特别是，我们计划确定突变体中的多巴胺转运体和/或突触小泡的pH是否发生了变化。这些研究将揭示多巴胺神经传递失调的潜在机制，并可能为开发治疗精神分裂症的新方法提供见解。 公共卫生相关性：我们建议表征精神分裂症小鼠模型22q11.2微缺失小鼠的多巴胺释放，以检验精神分裂症中多巴胺失调部分是由于突触前多巴胺终末的内在变化这一假说。

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.