GENETIC DETERMINANTS OF RECEPTOR FUNCTION IN SCHIZOPHRENIA

这个项目的总体目标是聚焦于两个分子靶标， 突触素I和α7神经元烟碱型乙酰胆碱受体AS 在项目1和3中确定的候选基因，它们介导神经元 精神分裂症的功能障碍。无论是积极的还是消极的结果都会 退还给其他调查人员，在那里他们将为 未来实验的设计和朝着隔离模型的方向发展 这种疾病的遗传决定因素。而临床和动物模型 研究可以提示功能障碍的神经机制，并牵涉到 特定的神经递质或受体，还有待于证明 特定分子靶标在结构或功能上的实际缺陷 与精神分裂症有关。神经元烟碱型乙酰胆碱 受体系统与听觉诱发的异常有关 项目1对精神分裂症患者及一级亲属的反应。 此外，一种特定的尼古丁受体Alpha7的水平降低，对 在大鼠和小鼠中都与听觉门控缺陷有关 项目3。我们的初步数据表明， 精神分裂症患者中这种受体的数量也很多。本项目 将测量受体水平、信使核糖核酸水平并检查编码序列 猪死后脑内α7基因多态性的研究 大量的精神分裂症患者和对照组。我们还发现了 与精神分裂症相关的显著表达缺陷 在突触蛋白中，突触蛋白调节着 神经递质。这样的缺陷可能会对 突触传递。这项工作将得到确认，区域 已确定存在缺陷。我们将与临床、动物密切合作 模型和连锁项目，其中可能建议其他候选基因 我们确定的任何遗传缺陷的遗传力可能在哪里 测试过。我们还将为其他生物提供分子生物学支持 GABAA-Beta1突变的功能分析等项目 项目2中连锁与精神分裂症的关联及分析 营养因子对异种移植的影响

The overall aim of this Project is to focus on two molecular targets, synapsin I and the alpha7 neuronal nicotinic acetylcholine receptor as candidate genes, identified in Projects 1 and 3, that mediate neuronal dysfunction in schizophrenia. Both positive and negative results will be returned to the other investigators where they will contribute to the design of future experiments and toward a model for isolation of the genetic determinants of this disease. While clinical and animal model studies can suggest a neuronal mechanism for dysfunction and implicate specific neurotransmitters or receptors, it remains to demonstrate that an actual deficit in structure or function in a specific molecular target correlates with schizophrenia. The neuronal nicotinic acetylcholine receptor system has been linked to abnormalities in auditory evoked responses in schizophrenics and first-degree relatives by Project 1. Further, decreased levels of a specific nicotinic receptor, alpha7, have been associated with an auditory gating deficit in both rats and mice by Project 3. Our preliminary data suggest that there may be a decreased population of this receptor in schizophrenics, as well. This Project will measure receptor levels, mRNA levels and examine the coding sequence of the alpha7 gene for polymorphisms in postmortem brain isolated from a large number of schizophrenics and controls. We have also found significant deficits, associated with schizophrenia, in the expression of the synapsins, synaptic proteins which regulate the release of neurotransmitters. Such a deficiency could have profound effects on synaptic transmission. This work will be confirmed and the regional deficiency determined. We will work closely with the clinical, animal model and linkage projects, where other candidate genes may be suggested and where the heritability of any genetic defects we identify can be tested. We will also provide molecular biology support for other projects such as functional analysis of the GABAa-beta1 mutation associated with schizophrenia by linkage in Project 2 and analysis of the effects of trophic factors on xenotransplants in Project 7.