Laboratory of Neurophysiology, ULB-Neuroscience Institute, Université Libre de Bruxelles.
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, B-1070, Belgium, and.
J Neurosci. 2019 Sep 18;39(38):7513-7528. doi: 10.1523/JNEUROSCI.2454-18.2019. Epub 2019 Jul 30.
The regulation of the striatum by the GPCR signaling through neuromodulators is essential for its physiology and physiopathology, so it is necessary to know all the compounds of these pathways. In this study, we identified a new important partner of the dopaminergic pathway: GPRIN3 (a member of the GPRIN family). GPRIN3 is highly expressed in the striatum but with undefined function. Cell sorting of medium spiny neurons (MSNs) in indirect MSNs and direct MSNs indicated the presence of the GPRIN3 gene in both populations with a preferential expression in indirect MSNs. This led us to generate GPRIN3 KO mice by CRISPR/Cas9 and test male animals to access possible alterations in morphological, electrophysiological, and behavioral parameters following its absence. 3D reconstruction analysis of MSNs revealed increased neuronal arborization in GPRIN3 KO and modified passive and active electrophysiological properties. These cellular alterations were coupled with increased motivation and cocaine-induced hyperlocomotion. Additionally, using a specific indirect MSN knockdown, we showed a preferential role for GPRIN3 in indirect MSNs related to the DR signaling. Together, these results show that GPRIN3 is a mediator of DR function in the striatum playing a major role in striatal physiology. The striatum is the main input of the basal ganglia processing information from different brain regions through the combined actions of direct pathway neurons and indirect pathway neurons. Both neuronal populations are defined by the expression of dopamine DR or DR GPCRs, respectively. How these neurons signal to the respective G-protein is still debatable. Here we identified GPRIN3 as a putative selective controller of DR function in the striatum playing a critical role in striatal-associated behaviors and cellular functions. This study represents the identification of a new target to tackle striatal dysfunction associated with the DR, such as schizophrenia, Parkinson's disease, and drug addiction.
通过神经调质的 GPCR 信号对纹状体的调节对于其生理学和病理生理学至关重要，因此有必要了解这些途径的所有化合物。在这项研究中，我们鉴定了多巴胺能途径的一个新的重要伙伴：GPRIN3（GPRIN 家族的成员）。GPRIN3 在纹状体中高度表达，但功能未知。间接 MSN 和直接 MSN 中的中间神经元（MSNs）的细胞分选表明，GPRIN3 基因存在于这两种群体中，在间接 MSN 中优先表达。这导致我们通过 CRISPR/Cas9 生成 GPRIN3 KO 小鼠，并测试雄性动物，以了解其缺失后形态、电生理和行为参数是否发生变化。MSNs 的 3D 重建分析显示，GPRIN3 KO 中神经元分支增加，并改变了被动和主动电生理特性。这些细胞变化与动机增加和可卡因诱导的过度活跃有关。此外，使用特定的间接 MSN 敲低，我们表明 GPRIN3 在与 DR 信号相关的间接 MSNs 中具有优先作用。总之，这些结果表明 GPRIN3 是纹状体中 DR 功能的介质，在纹状体生理学中起主要作用。纹状体是基底神经节的主要输入，通过直接途径神经元和间接途径神经元的共同作用，从不同脑区处理信息。这两种神经元群体分别由多巴胺 DR 或 DR GPCR 的表达定义。这些神经元如何向各自的 G 蛋白发出信号仍有争议。在这里，我们鉴定了 GPRIN3 作为纹状体中 DR 功能的一个假定选择性控制器，在与纹状体相关的行为和细胞功能中发挥关键作用。这项研究代表了鉴定一个新的靶点来解决与 DR 相关的纹状体功能障碍，如精神分裂症、帕金森病和药物成瘾。
