Basic to Clinical Molecular Neurobiology of Nicotinic Receptors in Schizophrenia

描述(由申请人提供)：该翻译联络中心的目标是(1)加强对α7烟碱型乙酰胆碱受体在大脑中的作用及其在精神分裂症中的功能障碍的基本分子和神经生物学特性；(2)利用这一生物学来继续开发新的治疗策略，以改进对精神分裂症患者的认知功能障碍和阴性症状的治疗(项目1)，以及(3)利用关于该受体的发育作用的新信息来发起对孕妇及其子女的围产期干预，以降低精神分裂症的风险(项目2)。该中心在精神分裂症神经功能障碍的动物模型中研究选择性α7尼古丁激动剂的潜在治疗效果，然后在精神分裂症患者的早期人类临床试验中进行研究。 它检查这种受体的基因CHRNA7，以确定它的表达是如何在 精神分裂症(项目3)和基因自然或故意突变的动物模型(项目4)。它决定了在人类和动物模型中，该基因的特定变异如何导致海马体和其他前脑区域抑制性神经元回路的发育障碍。然后，它检查了尼古丁激动剂的影响，这些影响可能会改变这些对发育的遗传影响。这些激动剂包括动物模型中选择性的α7尼古丁受体激动剂，以及人类和动物模型中的尼古丁本身，因为一些孕妇吸烟。由于胎儿大脑发育过程中的内源性配体似乎是胆碱，该中心还在孕妇及其新生儿和相关动物模型的临床试验中检查了补充胆碱对α7尼古丁受体功能和神经元发育的潜在有益影响。为了支持这些研究，该中心开发了对成人和婴儿的血液动力学和电生理抑制功能进行成像的策略，并开发了新的动物模型，包括将人CHRNA7转移到小鼠体内(项目5)和感染免疫反应导致的发育异常模型(项目6)。

DESCRIPTION (provided by applicant): The aims of this Translational Conte Center are (1) to enhance the basic molecular and neurobiological characterization of the role of the alpha7 nicotinic acetylcholine receptor in the brain and its dysfunction in schizophrenia; (2) to use this biology to continue development of a new therapeutic strategy to improve the treatment of cognitive dysfunction and negative symptoms in persons who have schizophrenia (Project 1), and (3) to use emerging information about the developmental role of the receptor to initiate a perinatal intervention for pregnant women and their children to decrease the risk of schizophrenia (Project 2). The Center investigates the potential therapeutic effects of selective alpha 7 nicotinic agonists in animal models of neuronal dysfunction in schizophrenia and then in early human clinical trials in patients with schizophrenia. It examines CHRNA7, the gene for this receptor, to determine how its expression becomes aberrant in schizophrenia (Project 3) and in animal models where the gene is naturally or intentionally mutated (Project 4). It determines in humans and animal models how specific variants in the gene result in dysfunction in the development of inhibitory neuronal circuitry in the hippocampus and other forebrain regions. It then examines the effects of nicotinic agonists that can potentially alter these genetic effects on development. These agonists include selective alpha 7 nicotinic receptor agonists in animal models and nicotine itself in both humans and animal models because some pregnant women smoke cigarettes. Because the endogenous ligand during fetal brain development appears to be choline, the Center also examines the potential beneficial effects of choline supplementation on alpha 7 nicotinic receptor function and neuronal development in a clinical trial in pregnant women and their newborn infants and in related animal models. To support these investigations, the Center develops strategies to image inhibitory function hemodynamically and electrophysiologically, in both adults and infants, and it develops new animal models, including the transfer of human CHRNA7 into mice (Project 5) and models of developmental abnormalities induced by the immune response to infections (Project 6).