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，典型和非典型抗精神病药物通过细胞群中不同的分子变化发挥作用，这些分子变化影响并参与纹状体信号传导。通过确定这些变化是什么，我们将确定与抗精神病药物治疗效果相关的共同信号通路。该Conte中心申请的项目1将专注于抗精神病药物给药诱导的纹状体细胞特异性mRNA翻译变化。为此，我们将使用我们新开发的翻译核糖体亲和纯化（TRAP）方法。在目的1中，我们将使用TRAP来确定纹状体多巴胺感受和多巴胺能细胞的主要群体中的mRNA翻译改变：纹状体黑质中棘神经元（MSNs）;纹状体MSNs;胆碱能中间神经元;黑质腹侧被盖区和黑质腹侧被盖区的多巴胺能神经元。 我们的初步TRAP研究表明，1-磷酸鞘氨醇（SIP），一种配体， 富含S1 P受体Gpr 6的MSNs可以改变MSNs中的钙水平和DARPP-32磷酸化水平。因此，S1 P和Gpr 6可能能够调节纹状体苍白球细胞的生理学和它们对抗精神病药物的反应。在目标2中，我们将使用遗传学，药理学和生物化学方法相结合的纹状体MSNs抗精神病药物治疗的反应中的81 P和Gpr 6信号转导的作用的特点。