Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits

作者全名："Zhang, Mengmeng; Kong, Xiangru; Chen, Jing; Liu, Wenqin; Liu, Can; Dou, Xiaoyun; Jiang, Lin; Luo, Yanmin; Song, Mingrui; Miao, Peng; Tang, Yong; Xiu, Yun"

作者地址："[Zhang, Mengmeng; Chen, Jing; Liu, Wenqin; Liu, Can; Dou, Xiaoyun; Song, Mingrui; Miao, Peng; Xiu, Yun] Chongqing Med Univ, Inst Life Sci, Mol Med Diagnost & Testing Ctr, Chongqing 400016, Peoples R China; [Kong, Xiangru] Chongqing Med Univ, Dept Pediat Surg Oncol, Childrens Hosp, Chongqing 400014, Peoples R China; [Jiang, Lin] Chongqing Med Univ, Lab Teaching Management Ctr, Chongqing 400016, Peoples R China; [Luo, Yanmin] Chongqing Med Univ, Dept Physiol, Chongqing 400016, Peoples R China; [Tang, Yong] Chongqing Med Univ, Dept Histol & Embryol, Chongqing 400016, Peoples R China"

通信作者："Xiu, Y (通讯作者)，Chongqing Med Univ, Inst Life Sci, Mol Med Diagnost & Testing Ctr, Chongqing 400016, Peoples R China.; Tang, Y (通讯作者)，Chongqing Med Univ, Dept Histol & Embryol, Chongqing 400016, Peoples R China."

来源：JOURNAL OF AFFECTIVE DISORDERS

ESI学科分类：PSYCHIATRY/PSYCHOLOGY

WOS号：WOS:000971999200001

JCR分区：Q1

影响因子：6.6

年份：2023

卷号：332

期号：　

开始页：72

结束页：82

文献类型：Article

关键词：Depression; CRS; NMDAR subunits; GluN3A; CRISPR; Cas9

摘要："Background: N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear. Methods: Firstly, expression of GluN3A was examined in a mouse model of depression induced by chronic re-straint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting. Results: GluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression. Limitations: The mechanism underlying GluN3A involvement in depression is not fully determined. Conclusions: Our data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs."

基金机构："National Natural Science Foundation of China [81301149, 81871073, 82171522]; Natural Science Foundation Project of Chongqing Science & Technology Commission [cstc2011jjA10066]; China Scholarship Council [202008500005]; Institute of Life Science,Chongqing Medical University [202004, 202006]; Chongqing Medical University"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (No. 81301149, No. 81871073 and No. 82171522) , Natural Science Foundation Project of Chongqing Science & Technology Commission (cstc2011jjA10066) , China Scholarship Council (202008500005) and the ""SKY project"" granted by the Institute of Life Science (202004 and 202006) , Chongqing Medical University."