MOUSE MOLECULAR AND NEUROBIOLOGICAL MODELS

主要由Conte Center应用程序的调查人员生成的数据提供了令人信服的证据， α 7烟碱乙酰胆碱受体亚单位是治疗性干预的潜在靶点， 精神分裂症这些数据包括以下观察结果，即α 7亚基的表达在 精神分裂症患者的海马体（项目1），CHRNA 7的遗传变异，编码 α 7亚基与精神分裂症和听觉感觉门控缺陷有关（项目3）， 听觉门控缺陷在精神分裂症患者中很常见，选择性α 7激动剂DMXB-A 改善门控缺陷（项目1）。此外，α 7选择性激动剂胆碱已被证明 在围产期给药时，改善人类婴儿的听觉门控（项目2）。惊人相似的数据 已经在小鼠身上获得。例如，我们已经在小鼠中表明：1）听觉门控缺陷是 与α 7受体表达减少相关，2）Chrna 7的遗传变异性与α 7受体表达减少相关， α 7受体表达和听觉门控缺陷，3）α 7受体选择性激动剂DMXB-A 改善门控缺陷，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α 7方面的相似性。 受体和听觉门控，以解决基本的生物学问题的具体作用， α 7受体和Chrna 7在正常和缺陷听觉门控中的作用。具体问题将是 在项目4中解决的是1）什么是分子机制（S），通过遗传变异在Chrna 7 导致α 7受体表达减少和听觉门控缺陷2）什么是神经生物学 α 7受体表达减少可能导致门控缺陷的机制？（3）什么是 围产期胆碱改善听觉门控的机制 项目4支持项目1和项目2的临床研究。它进行分子遗传学实验， 与项目3平行，并且它支持项目5和6中小鼠的表型。 相关性（参见说明）： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 症状和预防精神病的发展。该中心研究了一种烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计一种新的药物治疗， 精神分裂症和婴儿发育期间的预防性营养干预，这两者都激活了这一点。 rpr.pntnr

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. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this rpr.pntnr