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

我们的假设是，典型和非典型抗精神病药物通过影响和参与纹状体信号传导的细胞群中不同的分子变化发挥作用。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常见信号通路。Conte中心应用项目1将关注抗精神病药物引起纹状体细胞mRNA翻译的特异性变化。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Aim 1中，我们将使用TRAP来鉴定纹状体多巴胺感觉细胞和多巴胺能细胞主要群体中的mRNA翻译改变：纹状体中棘神经元（MSNs）；striatopallidal msn;胆碱能intemeurons;以及黑质致密部和腹侧被盖区的多巴胺能神经元。我们的初步TRAP研究已经揭示了鞘氨醇1-磷酸（SIP），一种用于蛋白质的配体

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.