Zheng Peng, Su Qian Peter, Jin Dayong, Yu Yinghua, Huang Xu-Feng
Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, Wollongong, NSW, Australia.
Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
Front Neurosci. 2020 Jun 23;14:642. doi: 10.3389/fnins.2020.00642. eCollection 2020.
Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R) - disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.
精神病一直被认为是一种神经元连接受损的疾病。多巴胺D2受体（D2R）与精神分裂症相关1（DISC1）复合物过度形成的证据，为精神病症状涉及的分子机制带来了新的视角。在此，我们研究了D2R激动剂喹吡罗诱导的过量D2R-DISC1复合物形成如何影响纹状体神经元的神经突生长和树突棘。利用荧光共振能量转移（FRET）、随机光学重建显微镜（STORM）和细胞穿透肽递送技术，对小鼠幼崽的培养纹状体神经元进行了研究。利用这些纹状体神经元，我们的研究表明：（1）D2R在培养的纹状体神经元的树突棘、神经突和胞体中与DISC1相互作用；（2）D2R和DISC1复合物在纹状体神经元的树突棘中聚集成簇，应用TAT-D2pep后复合物数量减少；（3）通过TAT-D2pep解开D2R-DISC1复合物可保护神经元形态和树突棘；（4）TAT-D2pep可防止神经突和树突棘丢失，并与突触素和PSD-95表达水平的恢复有关。此外，我们发现神经肽Y（NPY）和GSK3β参与了TAT-D2pep对纹状体棘状投射神经元神经突棘的保护作用。因此，我们的研究结果可能为精确治疗与精神分裂症相关的神经突棘缺陷提供一种新策略。
