Biochemical Mechanisms Mediating Cell Type-Specific Actions of Antipsychotic Drug

项目3将讨论CONTE中心的主要主题“确定抗精神病药物的细胞类型特异性作用”，主要是通过采用生化方法来表征关键信号蛋白，这些蛋白据信参与了抗精神病药物对皮质纹状体回路内神经功能的特定方面的影响。在目标1中，项目3将跟进最近与项目1合作进行的研究，这些研究发现，DARPP-32蛋白在所有纹状体中棘神经元(MSN)中高度丰富，通过一种涉及磷酸化/去磷酸化和核转位的新机制来调节染色质功能。其他研究表明，氟哌啶醇对MSN基因表达的调节作用需要DARPP-32。项目3将阐明DARPP-32‘S核功能在抗精神病药物作用中的作用。这些研究将与内斯特勒博士合作进行，并将与项目4的S对染色质重塑的研究整合在一起。在目标2中，项目3将在与Surmeier博士(项目5)合作的结果的基础上，确定氟哌啶醇所观察到的效应的生化基础，这些结果显示了典型的抗精神病药物氟哌啶醇对纹状体黑质和纹状体苍白质(MSNS)树突形态的具体影响。与项目2和项目5合作，这些研究将扩展到分析非典型抗精神病药物对MSN结构的生化影响，以及典型和非典型药物类别对皮质纹状体投射神经元的生化影响。在这些研究中，项目3将利用项目1和项目2的翻译图谱数据，以及项目4的基因表达数据，以确定与MSN结构控制有关的候选基因。在目标3中，项目3将与项目2合作开发新方法，以利用转基因小鼠模型的力量，对皮质纹状体回路中的特定神经细胞群进行系统的生化和蛋白质组学分析。项目3还将为其他项目正在进行的研究贡献生化专业知识，并根据新的发现，为孔特中心集体开展的未来研究做出贡献。

Project 3 will address the major theme of the Conte center "Identification of cell type-specific actions of antipsychotic drugs" by taking primarily biochemical approaches to characterize key signaling proteins believed to be involved in the effects of antipsychotic drugs on specific aspects of neuronal function within corticostriatal circuits. In Aim 1, Project 3 will follow up from recent studies carried out in collaboration with Project 1 that have found that the protein DARPP-32, which is highly enriched in all striatal medium spiny neurons (MSNs), regulates chromatin function through a novel mechanism involving phosphorylation/dephosphorylation and nuclear translocation. Other studies indicate that DARPP-32 is required for the effects of haloperidol on regulation of MSN gene expression. Project 3 will elucidate the role of DARPP-32's nuclear function in the actions of antipsychotic drugs. These studies will be carried out in collaboration with Dr. Nestler, and will be integrated with Project 4's studies of chromatin remodeling. In Aim 2, building on results obtained in collaboration with Dr. Surmeier (Project 5) that show specific effects of the typical antipsychotic haloperidol on the dendritic morphology of striatonigral and striatopallidal (MSNs), Project 3 will identify the biochemical basis for the observed effects of haloperidol. In collaboration with Projects 2 and 5, these studies will be expanded to analysis of the biochemical effects of atypical antipsychotic drugs on the structure of MSNs, as well as of both typical and atypical classes of drug on corticostriatal projection neurons. In these studies, Project 3 will make use of translational profiling data from Projects 1 and 2, as well as gene expression data from Project 4, to identify candidate genes involved in control of MSN structure. In Aim 3, Project 3 will work together with Project 2 in the development of new methods to exploit the power of transgenic mouse models to allow for systematic biochemical and proteomic analysis of specific neuronal cell populations within corticostriatal circuits. Project 3 will also contribute biochemical expertise to ongoing studies by the other projects, as well as contribute to future studies that are carried out collectively by the Conte Center as a result of new discoveries made.