GENETIC DETERMINANTS OF RECEPTOR FUNCTION IN SCHIZOPHRENIA

该项目的总体目标是关注两个分子靶点， 突触蛋白I和α 7神经元烟碱乙酰胆碱受体作为 候选基因，在项目1和3中确定，介导神经元 精神分裂症的功能障碍 积极和消极的结果都将 返回给其他研究人员，他们将有助于 设计未来的实验，并朝着一个模型的隔离 这种疾病的遗传决定因素。 虽然临床和动物模型 研究表明，神经元机制的功能障碍，并牵连 具体的神经递质或受体，它仍然证明， 特定分子靶点的结构或功能上的实际缺陷 与精神分裂症有关 神经元烟碱乙酰胆碱 受体系统与听觉诱发的异常有关， 精神分裂症患者和一级亲属的反应项目1。 此外，特异性烟碱受体α 7的水平降低， 与大鼠和小鼠的听觉门控缺陷有关， 项目3。 我们的初步数据表明， 在精神分裂症患者中这种受体的数量也是如此。 这个项目 将测量受体水平，mRNA水平，并检查编码序列 在死后大脑中分离的alpha 7基因的多态性， 大量的精神分裂症患者和对照组。 我们还发现 与精神分裂症相关的显著缺陷， 突触蛋白，突触蛋白调节释放 神经传递素 这种缺陷可能会对 突触传递 这项工作将得到确认， 缺陷确定。 我们将与临床、动物 模型和连锁项目，其中可能建议其他候选基因 我们发现的任何遗传缺陷的遗传性 测试. 我们还将为其他研究提供分子生物学支持。 GABAa-beta1突变的功能分析等项目 与精神分裂症相关的连锁分析 营养因子对项目7中异种移植的影响。

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.