He Yan, Li Yan, Chen Mozi, Pu Zhilan, Zhang Feiyang, Chen Long, Ruan Yang, Pan Xinran, He Chaoxiang, Chen Xingjun, Li Zhihui, Chen Jiang-Fan
School of Optometry and Ophthalmology and Eye Hospital, Institute of Molecular Medicine, Wenzhou Medical University Wenzhou, China.
Department of Geriatrics and Neurology, The 2nd Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University Wenzhou, China.
Front Mol Neurosci. 2016 Dec 26;9:151. doi: 10.3389/fnmol.2016.00151. eCollection 2016.
Striatal adenosine A receptors (ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D receptors (DRs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but evidence for these interactions is lacking. Using proximity ligation assay (PLA), we studied the subregional distribution of the AR-DR and AR-mGluR5 heterodimer complexes in the striatum and their adaptive changes over the random interval and random ratio training of instrumental learning. After confirming the specificity of the PLA detection of the AR-DR heterodimers with the AR knockout and DR knockout mice, we detected a heterogeneous distribution of the AR-DR heterodimer complexes in the striatum, being more abundant in the dorsolateral than the dorsomedial striatum. Importantly, habit formation after the random interval training was associated with the increased formation of the AR-DR heterodimer complexes, with prominant increase in the dorsomedial striatum. Conversely, goal-directed behavior after the random ratio schedule was not associated with the adaptive change in the AR-DR heterodimer complexes. In contrast to the AR-DR heterodimers, the AR-mGluR5 heterodimers showed neither subregional variation in the striatum nor adaptive changes over either the random ratio (RR) or random interval (RI) training of instrumental learning. These findings suggest that development of habit formation is associated with increased formation of the AR-DR heterodimer protein complexes which may lead to reduced dependence on DR signaling in the striatum.
纹状体腺苷 A 受体（ARs）可能通过受体 - 受体异二聚体与多巴胺 D 受体（DRs）和代谢型谷氨酸受体 5（mGluR5）进行功能相互作用，从而调节纹状体突触可塑性和工具性学习，但缺乏这些相互作用的证据。我们使用邻近连接分析（PLA）研究了纹状体中 AR - DR 和 AR - mGluR5 异二聚体复合物的亚区域分布及其在工具性学习的随机间隔和随机比率训练过程中的适应性变化。在用 AR 基因敲除和 DR 基因敲除小鼠证实 PLA 检测 AR - DR 异二聚体的特异性后，我们检测到纹状体中 AR - DR 异二聚体复合物分布不均，在背外侧纹状体比背内侧纹状体更丰富。重要的是，随机间隔训练后的习惯形成与 AR - DR 异二聚体复合物形成增加有关，背内侧纹状体有显著增加。相反，随机比率训练后的目标导向行为与 AR - DR 异二聚体复合物的适应性变化无关。与 AR - DR 异二聚体不同，AR - mGluR5 异二聚体在纹状体中既没有亚区域差异，在工具性学习的随机比率（RR）或随机间隔（RI）训练中也没有适应性变化。这些发现表明，习惯形成的发展与 AR - DR 异二聚体蛋白复合物形成增加有关，这可能导致纹状体对 DR 信号的依赖性降低。
