Identification of Cell Type-Specific Actions of Antipsychotic Drugs

描述（由申请人提供）：精神分裂症是最使人衰弱的精神疾病之一，影响全球约1%的人口。一些抗精神病药物是可用的，但这些往往是无效的，并不能治疗疾病的所有症状。我们需要新的治疗方法，但由于对这种复杂神经系统疾病的病因了解有限，以及对现有抗精神病药物的确切分子作用机制缺乏清晰的认识，新疗法的发现受到了阻碍。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性和混合细胞性质。因此，Conte中心提出的研究的主要目标是通过使用新型啮齿动物模型的创新方法来分析皮质纹状体回路中单个类型的神经元，从而全面了解抗精神病药物的细胞和分子作用。项目1的中心主任和负责人是Paul greenard（洛克菲勒大学）。其他项目负责人有：Nathaniel Heintz（项目2，洛克菲勒大学）；安格斯·奈恩（耶鲁大学项目3）；Eric Nestler（西奈山医学院项目4）；詹姆斯·萨梅尔（西北大学第五项目）。也将有一个动物核心，一个分子和生化试剂核心，和一个行政核心。所涉及的五个Pis已经建立了有效合作的历史，并将利用他们互补的专业知识和资源，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，拟成立的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。

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.