PHARMACOLOGY OF NICOTINIC RECEPTORS

该项目将复制和扩展CHRNA7基因多态与抑制功能障碍表型的关系，该表型通过精神分裂症患者和对照组受试者对重复听觉刺激的P50反应抑制来衡量。阿尔法7特异性激动剂将在精神分裂症患者身上进行测试，以确定它们是否使P50反应正常化，以及它们对精神分裂症的神经认知特征和临床症状的影响程度。我们已经获得了FDA的批准，可以给人类服用3-2，4-二甲氧基亚甲基Anabaseine，在初步的实验中，该药物改善了P50抑制的缺陷。α7尼古丁受体不仅在神经传递中发挥作用，我们通过抑制P50证明了这一点，而且它还具有重要的发育作用，我们观察到在带有acra7变体的动物模型中，海马区中间神经元的区域分布存在差异。由于纠正与Alpha7受体相关的神经传递缺陷不能解决这种发育作用，我们也将使用小鼠动物模型来 确定围产期α7激动剂治疗是否影响中间神经元的发育。为了扩展海马区的病理生理学，我们假设包括 在精神分裂症中发现的学习和记忆缺陷，我们现在显示了acra7(小鼠CHRNA 7)零突变小鼠的学习缺陷，以及在人类中P50异常与陈述性记忆下降相关的证据。我们提供了新的数据，即围产期补充胆碱导致acra7基因多态小鼠的后代对重复声音的海马体反应正常抑制。与瑞斯特雷波项目合作，我们将测量精神分裂症患者的嗅觉功能。在Ross的项目中，我们将记录P50抑制作为抑制功能的基本测量，以与他们在儿童和成人中的测量相关联。

This project will replicate and extend the relationship of genetic polymorphisms in CHRNA 7 to the phenotype of inhibitory dysfunction as measured by inhibition of the P50 response to repeated auditory stimuli in schizophrenic and control subjects. Alpha7-specific agonists will be tested in schizophrenics to determine if they normalize P50 response and to what extent they also affect the neurocognitive features and clinical symptoms of schizophrenia. We have received FDA approval for the administration of 3-2,4 dimethoxybenzylidene anabaseine to humans and in an initial experiment demonstrated that the drug improves deficient P50 inhibition. The alpha7 nicotinic receptor not only has a role in neurotransmission, which we demonstrate by P50 inhibition, but it also has a major developmental role that we have characterized by observing differences in the regional distribution of hippocampal interneurons in animal models with acra7 variants. Because correction of neurotransmission deficits related to alpha7 receptors does not address this developmental role, we will also employ mouse animal models to determine if alpha7 agonist treatment in the perinatal period affects the development of interneurons. To extend the hippocampal pathophysiology we have postulated to include the deficits in learning and memory found in schizophrenia, we now show deficits in learning in mice with the acra7 (murine CHRNA 7) null mutation, as well as evidence in humans that P50 abnormalities correlate with decreased declarative memory. We present new data that perinatal choline supplementation to mice with acra7 polymorphisms results in offspring with normal inhibition of the hippocampal response to repeated sounds. In conjunction with Project by Restrepo, we will measure olfactory function in schizophrenics. For Project by Ross, we will record P50 inhibition as a basic measure of inhibitory function to be related to their measurements in children and adults.