Identification of Cell Type-Specific Actions of Antipsychotic Drugs

描述(申请人提供)：精神分裂症是最令人衰弱的精神疾病之一，影响全球约1%的人口。有许多抗精神病药物可用，但这些药物往往无效，并不能治疗疾病的所有症状。需要新的治疗方法，但由于对这种复杂神经疾病的病因学了解有限，以及对现有抗精神病药物的确切分子作用机制缺乏明确了解，这些药物的发现一直受到阻碍。确定抗精神病药物作用的分子机制的主要限制之一是中枢神经系统的异质和混合细胞性质。因此，孔特中心拟议研究的主要目标是通过创新方法实现对抗精神病药物的细胞和分子作用的全面了解，这些方法使用新的啮齿动物模型来分析皮质-纹状体回路中的个别类型的神经元。项目1的中心主任和负责人是Paul Greengard(洛克菲勒大学)。其他项目负责人是：纳撒尼尔·海因茨(项目2，洛克菲勒大学)、安格斯·奈恩(项目3，耶鲁大学)、埃里克·内斯特勒(项目4，西奈山医学院)和詹姆斯·苏梅尔(项目5，西北大学)。还将有一个动物核心，一个分子和生化试剂核心，以及一个管理核心。所涉及的五个私人投资机构已有有效合作的既定历史，并将利用其互补的专门知识和资源，在拟议的研究中采取多学科方法。通过使用生化、细胞生物学、分子、电生理、结构和行为分析，拟建的Conte中心将更全面地了解抗精神病药物在皮质纹状体回路中的细胞和分子作用。 公共卫生相关性：与公共健康相关：精神分裂症是一种衰弱的精神疾病，需要新的治疗方法。这个康特中心将表征抗精神病药物对精神分裂症所涉及的特定神经元亚型特性的影响，使人们能够完全了解这些药物的正常和不适应行为，并导致更好的治疗方法，更高的疗效和更少的副作用。

DESCRIPTION (provided by applicant): Schizophrenia is one of the most debilitating psychiatric disorders, affecting approximately 1% of the population worldwide. A number of antipsychotic drugs are available but these are often ineffective and do not treat all the symptoms of the disease. New therapeutics are needed but their discovery has been hampered by a limited understanding of the etiology of this complex neurological disorder, and a lack of clear understanding of the precise molecular mechanisms of action of available antipsychotic drugs. One of the major limitations in identifying the molecular mechanisms of antipsychotic drug action has been the heterogeneous and intermixed cellular nature of the central nervous system. The major goal of the proposed studies in the Conte Center is therefore to achieve a complete understanding of the cellular and molecular actions of antipsychotic drugs through innovative approaches that use novel rodent animal models to allow analysis of individual types of neurons within cortico-striatal circuits. The Center Director and leader of Project 1 is Paul Greengard (Rockefeller University). The other Project leaders are: Nathaniel Heintz (Project 2, Rockefeller University); Angus Nairn (Project 3, Yale University); Eric Nestler (Project 4, Mount Sinai Medical School); and James Surmeier (Project 5, Northwestern University. There will also be an Animal Core, a Molecular & Biochemical Reagents Core, and an Administrative Core. The five Pis involved have an established history of effective collaboration and will use their complementary expertise and resources to take a multi-disciplinary approach in the proposed research. Through the use of biochemical, cell biological, molecular, electrophysiological, structural and behavioral assays, the proposed Conte Center will achieve a fuller understanding of the cellular and molecular actions of antipsychotic drugs in the cortico-striatal circuits. PUBLIC HEALTH RELEVANCE: Relevance to public health: Schizophrenia is a debilitating psychiatric disorder, and new therapies are needed. This Conte Center will characterize the effects of antipsychotic drugs on the properties of specific neuronal subtypes involved in schizophrenia, allowing for a complete understanding of the normal and maladaptive actions of these drugs, and leading to better therapies with higher efficacy and fewer side-effects.