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

我们的假设是，典型的和非典型的抗精神病药物通过影响和参与纹状体信号的细胞群体中不同的分子变化来发挥作用。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有关的常见信号通路。该中心应用的项目1将集中在抗精神病药物治疗引起的纹状体细胞特异性mRNA翻译的变化。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。在目标1中，我们将使用TRAP来识别纹状体多巴胺能和多巴胺能神经元的主要群体：纹状体黑质中棘神经元(MSN)、纹状体苍白质MSN、胆碱能中间神经元以及黑质致密部和腹侧被盖区的多巴胺能神经元。我们的初步陷阱研究表明，1-磷酸鞘氨醇(Sphingosine 1-Phate，SIP)是一种 纹状体桥本MSN丰富的S1P受体Gpr6可以改变MSN中的钙水平和DARPP-32磷酸化水平。因此，S1P和Gpr6可能能够调节纹状体苍白质细胞的生理及其对抗精神病药物的反应。在目标2中，我们将结合遗传学、药理学和生物化学方法研究81P和Gpr6信号在纹状体MSN对抗精神病药物治疗的反应中的作用。

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.