Striatal Cell-specific Analysis of the Molecular Mechanisms of Antipsychotic Drug

抗精神病药物分子机制的纹状体细胞特异性分析

• 批准号: 8150110
• 负责人: PAUL GREENGARD
• 金额: $ 26万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150110
• 关键词: Affect; Affinity Chromatography; Antipsychotic Agents; Behavioral; Biochemical; Calcium; Cell physiology; Cells; Corpus striatum structure; Dopaminergic Cell; Dorsal; Genetic; Genetic Translation; Immunohistochemistry; In Situ Hybridization; Knock-out; Ligands; Link; Mental disorders; Messenger RNA; Methodology; Molecular; Molecular Analysis; Neurons; Phosphorylation; Population; Public Health; Ribosomes; Role; Schizophrenia; Signal Pathway; Signal Transduction; Sphingosine-1-Phosphate Receptor; Substantia nigra structure; Therapeutic Effect; Translating; Ventral Striatum; Ventral Tegmental Area; atypical antipsychotic; cholinergic; cholinergic neuron; dopaminergic neuron; novel therapeutics; pars compacta; receptor; response; sphingosine 1-phosphate

It is our hypothesis that typical and atypical antipsychotic drugs exert their actions via distinct molecular changes in cell populations that impinge upon and participate in striatal signaling. By identifying what these changes are, we will identify common signaling pathways that are linked to the therapeutic effects of antipsychotic drugs. Project 1 of this Conte center application will focus on striatal cell-specific changes in mRNA translation induced by antipsychotic drug administration. For this purpose we will use our newly developed Translating Ribosome Affinity Purification (TRAP) methodology. In Aim 1 we will use TRAP to identify mRNA translational alterations in the major populations of striatal dopaminoceptive and dopaminergic cells: striatonigral medium spiny neurons (MSNs); striatopallidal MSNs; cholinergic intemeurons; and dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area. Our preliminary TRAP studies have revealed that sphingosine 1-phosphate (SIP), a ligand for the striatopallidal MSN-enriched S1P receptor Gpr6, can alter both calcium levels and DARPP-32 phosphorylation levels in MSNs. Thus, S1P and Gpr6 may be capable of modulating striatopallidal cell physiology and their response to antipsychotic drugs. In Aim 2, we will characterize the role of 81P and Gpr6 signaling in the response of striatal MSNs to antipsychotic drug treatment using a combination of genetic, pharmacological, and biochemical approaches.

我们的假设是，典型和非典型的抗精神病药通过影响并参与纹状体信号传导的细胞群体的明显分子变化来发挥其作用。通过确定这些变化是什么，我们将确定与抗精神病药的治疗作用相关的常见信号通路。该孔戴中心应用的项目1将重点介绍抗精神病药剂诱导的mRNA翻译中的纹状体细胞特异性变化。为此，我们将使用新开发的翻译核糖体亲和力纯化（TRAP）方法。在AIM 1中，我们将使用陷阱来鉴定纹状体多巴胺感受和多巴胺能细胞的主要种群中的mRNA平移变化：纹状体中培养基神经元（MSNS）；纹状体金属MSN；胆碱能源；黑质底层紧凑型和腹侧对段区域的多巴胺能神经元。 我们的初步陷阱研究表明，1-磷酸盐（SIP），一种配体的配体 富含MSN的S1P受体GPR6可以改变MSN的钙水平和DARPP-32磷酸化水平。因此，S1P和GPR6可能能够调节纹状体金细胞生理及其对抗精神病药的反应。在AIM 2中，我们将表征81p和GPR6信号传导在纹状体MSN对抗精神病药物治疗响应中使用遗传，药理和生化方法的作用。