OLFACTORY FUNCTIONS

精神分裂症是一种多基因疾病，其中每个基因突变都有助于疾病原型的行为表型子集。为了检验特定突变导致精神分裂症的假设，将由基因突变引起的神经元功能改变与特定行为表型相关联是至关重要的。在这里，我们建议功能研究嗅觉功能障碍的分子基础，在精神分裂症患者的一个重要部分中发现的感觉表型。我们推测，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降低。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，而且还通过利用神经元培养从死后组织，我们提出了初步的可行性数据显示，我们可以记录这些细胞的烟碱反应，利用钙成像技术。使用人类嗅球神经元的文化，我们建议测试的假设，改变α 7烟碱受体启动子导致功能的变化，嗅球中间神经元的反应乙酰胆碱，有助于嗅觉功能障碍的精神分裂症。在具有改变表达的同源和敲除小鼠中的平行实验 将测试对乙酰胆碱的反应性改变与嗅觉行为之间的联系。这些实验将是第一个研究精神分裂症患者和对照组神经元功能的实验。

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.