Elucidating Aberrant Dopamine Release in Schizophrenia

描述（由申请人提供）：精神分裂症是一种具有重大公共卫生意义的衰弱性疾病。虽然精神分裂症的病因尚不清楚，但多巴胺系统的过度活跃在精神分裂症相关的阳性症状中的作用长期以来一直从对D2多巴胺受体拮抗剂的抗精神病反应中推断出来，因为多巴胺受体拮抗剂安非他明可能是精神性的。最近的成像研究表明，在精神分裂症患者中，安非他明诱导的多巴胺释放增强，但其潜在机制尚不清楚，部分原因是缺乏动物模型。22q11.2微缺失的个体具有认知缺陷和患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）是合成的人类22 q11.2 1.5 Mb微缺失，显示出与精神分裂症相似的特征。我们的初步数据表明，有一个改变多巴胺释放急性皮质纹状体切片。我们假设精神分裂症中多巴胺失调部分是由于突触前多巴胺末梢的内在变化。为了验证这一假设，我们建议在这个小鼠模型中的纹状体和前额叶皮层中表征多巴胺的储存、释放和可塑性。我们将采用快速扫描循环伏安法和一种新的光学成像方法，使多巴胺的储存和释放在个别终端可视化，以阐明可能导致精神分裂症异常多巴胺释放的机制。特别是，我们计划确定是否多巴胺转运蛋白和/或突触囊泡pH值已被改变的突变体。这些研究将揭示多巴胺神经传递失调的潜在机制，并可能为精神分裂症治疗新方法的发展提供见解。 公共卫生相关性：我们建议在精神分裂症的小鼠模型，22q11.2微缺失小鼠，多巴胺释放的特点，以测试的假设，即多巴胺失调精神分裂症的部分结果从突触前多巴胺终端的内在变化。

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.