Comprehensive Report: Focusing on the same field of small glial cell synapses, Nature withdraws the article first, science later.

On February 5, 2020, Professor Michael Carroll of the Boston Children's Hospital of Harvard Medical School withdrew the article published in 2017 in the journal Nature. In his statement of retraction, he said that researchers could not repeat the key data. Most importantly, figures. 1a, B, D and 3a in the original text, The results of sequencing structure and behavioral experiment of microglia isolated from 564ig I autoimmune mice (564 mice for short) could not be repeated, so the manuscript was withdrawn.let's look at the first question 1) In the original text, through multiple behavioral experiments, the researchers found that 564 mice of 12 weeks old had the phenotypes of aggressive enhancement, anxiety like behavior, social disorder and cognitive impairment, and then intraperitoneal injection of type I interferon receptor targeted monoclonal antibody every four days. After one month, the above behavior phenotypes of 564 mice were reversed, which means that IFN-I receptor targeted monoclonal antibody can be treated The anxiety and cognitive impairment of the mice were observed.this is the result of figures. 1a, B, D in the original text, but it can not be repeated.so what is the problem? The background of 564ig I autoimmune mice is C57BL / 6 mice. It has a heritable insertion site in the variable region of immunoglobulin heavy and light chain, and can produce autoantibody 564, which is commonly used as an animal model of systemic lupus erythematosus.the first possibility is that the nervous system related behavioral phenotypes of 564 mice do not exist, which is wrong from the beginning.we further searched for the behavioral phenotypes of 564 mice, but we have not seen any evidence of the behavioral phenotypes of the model mice in the nervous system, but we can not rule out that this article is the first report.the second possibility is that there are behavioral phenotypes related to nervous system in 564 mice, but these behaviors may not be reversed by monoclonal antibody targeting IFN-I receptor.I think the second possibility is relatively large (the above two possibilities are also some conjectures in this paper).the second question (figs3a, b) : transcriptome analysis of microglia in cortex and hippocampus of 564ig I autoimmune mice and wild-type mice receiving type I interferon receptor targeted monoclonal antibody showed that genes related to interferon response were significantly up-regulated in 564 mice, which were related to cell metabolism, purinergic signal transduction, interferon type I production, phagocytosis and lysis The enzyme body tissue and so on.this is the result of FIGS. 3a, B in the original text, which can not be repeated.therefore, IFN-I receptor may not be a signal pathway to promote the activity of microglia in systemic lupus erythematosus model.however, the data in these two graphs do not relate to the experimental results of microglia phagocytosis of synapses, and the retraction statement does not further question the role of microglia in synaptic reduction in systemic lupus erythematosus models.behind the withdrawal: there is a common problem in the graph of type I IFN receptor antagonist anifrolumab that can not repeat the results, that is, type I IFN receptor.anifromumab is a monoclonal antibody targeting interferon receptor, which blocks the activity of all type I interferon including IFN - α, IFN - β and IFN - ω.for the treatment of moderate to severe systemic lupus erythematosus, developed by the global pharmaceutical giant AstraZeneca. Currently, anifrolumab has completed phase III clinical trials and achieved good results.on February 7, 2020, Gu Yan research team of Medical College of Zhejiang University published an article in the journal Science, which found that complement mediated microglia phagocytosis synaptic regulation of memory forgetting.the researchers conducted an interesting experiment, in which the mice showed obvious rigidity after fear training (receiving foot shock). It was further found that the rigidity behavior was more obvious on the fifth day, but significantly weakened after the 35th day, which indicated that under normal circumstances, the mice would forget those fearful memories.but all of these changed after microglia knockout - the rigidity behavior of microglia was still serious 35 days after gene knockout or pharmacology knockout, indicating that the memory forgetting of mice was impaired, and microglia might be involved in it.previous studies have shown that memory retrieval requires the activation of imprinted cells.compared with the 5th day of fear training, the activation number of imprinted cells in hippocampus of mice was decreased on the 35th day after training, but it was significantly increased after microglia knockout.that is to say, microglia mediate the process of memory forgetting by regulating the activation of imprinted cells.the researchers did not focus on the structure of imprinted cells at the submicron level, but on the synapses at the ultrastructural level.the synaptic connection between memory imprinted cells is the key structure for memory storage.in addition, complement mediated phagocytic synapses of microglia are also the focus of current research.therefore, the mechanism of microglia regulating imprinted cells is on phagocytic synapses.through microscopic imaging technology, they found that there were presynaptic and postsynaptic structures in the "stomach" of microglia, and the complement component C1q was also included in it, which indicated that microglia did phagocytize synapses in the process of memory forgetting, and complement protein might promote this process.the researchers further used AAV virus to overexpress CD55 (a classical complement and alternative complement pathway), On the 35th day after training, the stiff behavior of mice was still obvious, the number of activation of imprinted cells in hippocampus increased, and microglia phagocytized fewer neuronal structures (why not synaptic structure, because the virus in this article uses syn as the promoter and mainly expresses the neural structure).therefore, the results of this virus experiment can only show that the contact between microglia and neuronal structure is reduced.but this experiment further shows that complement pathway is involved in microglia phagocytosis synapses.References: 1. Microglia medium obtaining via complex dependent synaptic elimination2. Microglia dependent synapse loss in type I interfere mediated lupus