MOUSE MOLECULAR AND NEUROBIOLOGICAL MODELS

主要由Conte Center应用程序的研究人员生成的数据提供了令人信服的证据，表明α7烟碱型乙酰胆碱受体亚单位是精神分裂症治疗干预的潜在目标。这些数据包括观察到精神分裂症患者海马区α7亚单位的表达减少(项目1)，编码α7亚单位的基因CHRNA7的遗传变异与精神分裂症和听觉感觉门控缺陷有关(项目3)以及 听觉门控缺陷在精神分裂症患者中很常见，选择性Alpha7激动剂DMXB-A改善了门控缺陷(项目1)。此外，Alpha7选择性激动剂胆碱已被证明在围产期给药时可以改善人类婴儿的听觉门控(项目2)。在老鼠身上也获得了惊人的相似数据。例如，我们已经在小鼠身上证明，1)听觉门控缺陷与α7受体表达减少有关，2)克莱纳7基因的遗传变异性与表达减少有关 这些研究包括：α7受体的表达和听觉门控缺陷，3)α7受体选择性激动剂DMXB-A改善门控缺陷，以及4)围产期胆碱改善门控缺陷小鼠品系的听觉门控。在项目4中，我们将利用人类和小鼠在alpha7受体和听觉门控方面的相似性来解决有关alpha7受体和chrna7在正常和缺陷听觉门控中的具体作用的基本生物学问题。将在项目4中解决的具体问题是：1)是什么分子机制(S)通过什么在克莱纳7号的遗传变异 导致α7受体表达减少和听觉门控缺陷2)阿尔法7受体表达减少可能导致听觉门控缺陷的神经生物学机制是什么？3)围产期胆碱改善听觉门控的机制是什么？ 项目4支持项目1和项目2的临床研究。它与项目3并行进行分子遗传学实验，并支持项目5和6中的小鼠表型。

Data generated largely by investigators of this Conte Center application provide compelling evidence that the alpha 7 nicotinic acetylcholine receptor subunit is a potential target for therapeutic intervention in schizophrenia. These data include the observations that the expression of the alpha7 subunit is reduced in the hippocampus of schizophrenics (Project 1), genetic variants in CHRNA7, the gene that encodes the alpha7 subunit, are associated with schizophrenia and auditory sensory gating deficits (Project 3) and auditory gating deficits are common among schizophrenics and the selective alpha7 agonist DMXB-A improves gating deficits (Project 1). In addition, the alpha7 selective agonist choline has been shown to improve auditory gating in human infants when administered perinatally (Project 2). Strikingly similar data have been obtained in mice. For example, we have shown in mice that 1) auditory gating deficits are correlated with reduced alpha7 receptor expression, 2) genetic variability in Chrna7 is linked to reduced expression of alpha7 receptors and auditory gating deficits, 3) the alpha7 receptor selective agonist DMXB-A improves gating deficits and, 4) perinatal choline improves auditory gating in a gating deficient mouse strain. In Project 4 we will take advantage of the similarities between human and mouse with respect to alpha7 receptors and auditory gating to address fundamental biological questions regarding the specific role of alpha7 receptors and Chrna7 in normal and deficient auditory gating. The specific questions that will be addressed in Project 4 are 1) what is the molecular mechanism(s) through which genetic variability in Chrna7 leads to reduced expression of alpha7 recptors and auditory gating deficits 2) what is the neurobiological mechanism by which reduced expression of alpha7 receptors might lead to gating deficits? and 3) what is the mechanism through which perinatal choline improves auditory gating? Project 4 supports the clinical research of Projects 1 and 2. It performs molecular genetics experiments in parallel with Project 3, and it supports the phenotyping of mice in Projects 5 and 6.