Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis
Abstract
Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Ying-Han Wang
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Chong-Lei Fu
Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University
Lin-Bo Chen
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Chu-Yi Zhang
Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences
Jian-Shan Chen
Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital
Qiao-Ming Zhang
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Yirui Liang
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Rui-Lan Yang
Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital
Yu Li
Ya-Ni Zhang
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Yi-Nuo Han
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Zhen-Liang Yuan
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Yi-Ni Chen
State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University
Haimei Li
Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, The Key Laboratory of Mental Disorder Management in Zhejiang Province
Yanmeng Pan
Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, The Key Laboratory of Mental Disorder Management in Zhejiang Province
Shaohua Hu
Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, The Key Laboratory of Mental Disorder Management in Zhejiang Province
Ming Li
Li-Ping Cao
Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences
Jun Yao
Key Lab of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering