P2 - Role of mGluR5/CK1-CK2/DARPP-32 Pathway in Psychostimulant Effects

DARPP-32是生理条件下纹状体信号的关键整合者，在精神兴奋剂的情况下也是如此。除多巴胺外，谷氨酸等多种神经递质也作用于DARPP-32下游信号。我们的研究已经证明了多种信号通路在药物滥用行为中聚集在DARPP-32上的重要性，最近我们开发了最先进的技术，证明这些信号事件在不同亚群的中棘神经元（msn）中被特异性调节，这些亚群不同地表达Dl和D2类型的多巴胺受体。我们正在进行的研究将集中在mGluRS（一种重要的GPCR，参与谷氨酸依赖的DARPP-32调节）和两种激酶CKI和CK2的研究上。CKI在mGluR5/DARPP-32通路中起关键作用，CK2对DARPP-32核转运的调控至关重要。我们已经为这三个目标中的每一个产生了新的小鼠系，这将使我们不仅能够研究体内精神兴奋剂的影响，而且还可以评估D1-和d2 - msn在这些现象中的相对重要性。为了解决这些问题，我们在计划计划奖助金的计划2中提出三个目标。

It is well established that DARPP-32 is a key integrator of striatal signaling in physiological conditions as well as in the context of psychostimulants. Beside dopamine, various neurotransmitters such as glutamate act on and modify DARPP-32 downstream signaling. Our studies have demonstrated the importance of multiple signaling pathways converging on DARPP-32 in the action of drugs of abuse, and recently we have developed state-of-the-art technologies proving that these signaling events are specifically regulated in different sub-populations of medium spiny neurons (MSNs) that differentially express Dl and D2 types of dopamine receptor. Our ongoing research will focus on studies of mGluRS, an important GPCR invovled in glutamate-dependent DARPP-32 regulation, and two kinases, CKI and CK2. CKI is a crucial player in the mGluR5/DARPP-32 pathway and CK2 is essential for regulation of DARPP-32 nuclear trafficking. We have generated novel mouse lines for each of the three proposed Aims that will allow us not only to study the impact of psychostimulants in vivo but also to evaluate the relative importance of D1- and D2-MSNs in these phenomena. To address these questions we propose three Aims in Project 2 of the Program Project Grant. In Aim I we will study the role of the newly discovered mGluRS regulator Norbin in the actions of psychostimulants. In Aim II we will study the role of CK1 in the mGluRS/DARPP-32 pathway in vivo. We will also further charcterize the CK16 over expressing mice that present some behavioral features that ressembles ADHD. We will further address differences observed between Dl and D2 receptor pathways. In Aim III we will study the role of CK2 in the actions of psychostimulants, in both Dl and D2-MSNs using specific KO strategies. Results from this Project will complement the other two Projects of this Program Project grant. In addition we will also carry out a number of collaborative studies with Projects 1 and 3, including studies involving spine morphology with Project 1 and phosphoproteomic studies and behavioral studies with Project 3.