OLFACTORY FUNCTIONS

精神分裂症是一种多基因疾病，其中每个基因突变都会导致该疾病典型行为表型的亚群。为了验证特定突变导致精神分裂症的假设，必须将基因突变引起的神经元功能改变与特定行为表型联系起来。在这里，我们建议从功能上研究嗅觉功能障碍的分子基础，这是一种在精神分裂症患者中发现的感觉表型。我们假设α 7烟碱乙酰胆碱受体启动子的突变导致大量精神分裂症患者区分密切相关气味的能力下降。我们表明，我们可以研究人类嗅球神经元，不仅使用神经解剖学技术，而且还可以利用死后组织中的神经元培养，我们提出了初步的可行性数据，表明我们可以利用钙成像技术记录这些细胞中的尼古丁反应。利用培养的人类嗅球神经元，我们提出测试α 7烟碱受体启动子的改变导致嗅球中间神经元对乙酰胆碱反应的功能改变，从而导致精神分裂症患者嗅觉功能障碍的假设。基因和基因敲除小鼠表达改变的平行实验

Schizophrenia is a multigenic disorder where each genetic mutation contributes to subsets of the behavioral phenotypes prototypical of the disease. In order to test the hypothesis that a particular mutation contributes to schizophrenia it is essential to associate alterations in neuronal function caused by gene mutations with specific behavioral phenotypes. Here we propose to study functionally the molecular basis for olfactory dysfunction, a sensory phenotype found in a substantial fraction of schizophrenics. We hypothesize that a mutation in the promoter for the alpha7 nicotinic acetylcholine receptor contributes to diminished ability to differentiate between closely related odorants by a substantial number of schizophrenics. We show that we can study olfactory bulb neurons in humans, not only using neuroantomical techniques, but also by utilizing neuronal cultures from postmortem tissue, and we present preliminary feasibility data showing we can record nicotinic responses in these cells utilizing calcium imaging techniques. Using human olfactory bulb neurons in culture, we propose to test the hypothesis that alterations in the alpha7 nicotinic receptor promoter causes functional changes in the responses of olfactory bulb interneurons to acetylcholine that contribute to olfactory dysfunction in schizophrenics. Parallel experiments in congenic and knockout mice with altered expression of the alpha7 acetylcholine receptor will test the link between altered responsiveness to acetylcholine and olfactory behavior. These experiments will be the first to study neuronal function in schizophrenics and controls.