Anxiety disorders may be the fault of abnormal neuronal pruning caused by the immune system!

Learn about the latest progress in neuroscience ● click the blue word to pay attention to us ● a large number of nerve cells proliferate during nerve development and migrate to the neural outer tube, and locate in different brain regions. At the same time, about half of the nerve cells die physiologically.in these processes, cell stress produces a large number of by-products, DNA damage, cell debris, all of which may activate immune signals and damage the brain.melanoma deficiency factor (aim2) is a member of interferon induced HIN-200 protein family. It is a pattern recognition receptor (PRR) and a tumor related factor widely studied.as an intracellular DNA receptor, it can sense the double stranded DNA released into the cytoplasm when DNA virus or bacterial infection occurs, and further binds to the adaptor protein ASC to form aim2 inflammatory bodies.the activation of aim2 inflammasome plays an important role in host anti infection immunity, but the pyrolytic cell death induced by aim2 is caspase-1 dependent [1].in April 2020, the John R. Lukens research team of the center for brain immunology and glial cell research of the University of Virginia published an article in the journal Nature, revealing the immune activation mechanism of abnormal neural pruning during development that can cause adult anxiety [2].ASC spots are important precursor proteins of inflammatory bodies, which can activate the precursor of Caspase-1 to caspase-1, and then exert immune function [3].Using ASC report mice, researchers found that on the 5th day after birth, high levels of DNA damage and cell death occurred during this period, and there were a lot of ASC spots in the cortex and cerebellum, but hardly in the peripheral mature immune organs.further, adult caspase-1 knockout mice and aim2 knockout mice significantly reduced the time of entering the open arm in the elevated experiment, the number of times of entering the central area and the residence time in the open field experiment were also significantly reduced, showing obvious anxiety like behavior.the picture is quoted from [2]. The behavioral inflammatory bodies of aim2, caspase-1 and NLRP3 knockout mice are multi protein complexes, which usually contain receptor protein, adaptor protein ASC and downstream caspase-1.at present, there are five kinds of inflammatory corpuscles, namely nlrp1, NLRP3, nlrc4, ipaf and aim2.among them, NLRP3 can induce the activation of inflammatory corpuscles, and the endogenous molecules released by neuronal death respond during brain development [4].however, the researchers found that there was no anxiety like behavior in adult NLRP3 knockout mice, which indicated that NLRP3 did not participate in the development of inflammatory body activation to cause anxiety like behavior in mice.however, how do these ASC spots form during brain development? On the 5th day after birth, ASC spots in the cerebellum of aim2 knockout mice decreased significantly, indicating that aim2 was involved in the formation of ASC spots.in addition, studies have shown that DNA damage commonly occurring in the developing brain can trigger the activation of aim2 inflammasome.immunofluorescence assay showed that ASC spots formed during brain development were close to the cells with DNA damage.it was further found that the number of cells with DNA damage and the formation of ASC spots in wild-type mice on day 5 after birth were also increased; however, in aim2 knockout mice, the number of cells with DNA damage increased, but the formation of ASC spots decreased. these results suggest that DNA damage stimulates the inflammatory bodies of aim2 during brain development, and disrupts this pathway, leading to anxiety like behavior. immunofluorescence showed that compared with wild-type mice, the expression of DNA damage markers in almost whole brain of mice with caspase-1 and gsdmd knockout was increased. was further confirmed by single cell DNA gel electrophoresis of single cell DNA damage. inflammatory corpuscles of aim2 can induce scorch cell death in two ways: first, the classical pathway can activate caspase-1, and activated caspase-1 can promote the secretion of inflammatory factors IL-1 β and IL-18, and induce cell scorch; the other is that Caspase-1 activated by non classical pathway can promote the secretion of decortin D and cause scorch. adult IL-1 β and IL-18 knockout mice did not exhibit anxiety like behavior. however, there is another possibility that there is a compensatory effect after the knockout of IL-1 β and IL-18. Therefore, the researchers found that the MyD88 knockout mice did not show anxiety like behavior, which indicated that there was no compensatory effect (MyD88 is an essential molecule for IL-1R and IL-18R signal transduction). however, anxiety like behavior was observed in gsdmd knockout mice. therefore, these results suggest that the behavioral disorder caused by aim2 knockout is mainly caused by the nonclassical activation of deskin D. although half of the neurons die during brain development, this death is actually a kind of neuronal pruning, which is conducive to strengthening neuronal connections [5]. damage to this type of neurons in the development stage will cause neurological dysfunction after pruning, and DNA damage in the cerebellum can cause neuronal death. in order to further study the role of aim2 inflammatory bodies in neuronal death, the number of cerebellar neuronal death in aim2 knockout mice decreased on the 5th day after birth, as well as in gsdmd and caspase-1 knockout mice. however, the destruction of aim2 inflammasome signaling pathway can not completely block these neuronal death, which indicates that there may be other new forms of cell death. Where do these aim2 come from during brain development? Based on this problem, the researchers used in situ hybridization to find that aim2 was expressed in neurons, microglia and astrocytes during development. mice that specifically knock out caspase-1 on microglia do not show anxiety like behavior in adulthood, while mice with caspase-1 specific knockout of nestin CRE (expressed on neurons, astrocytes and oligodendrocytes) can show touch anxiety like behavior in adulthood. in general, this study reveals how DNA damage in the brain immune system during development leads to impairment of central nervous system development and anxiety disorder. References: 1. Hornung, V. et al. Aim2 recognizing cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514 – 518 (2009). 2. Aim2 inflammasome surveillance of DNA damage shapes neurodevelopment 3. Tzing, T. C. et al. A fluorescent reporter mouse for inflammasome assembly demontrates an important role for cell-bound and free ASC specks during in vivo infection. Cell Rep. 16, 571–582 (2016)4.Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015)5.Yamaguchi, Y. & Miura, M. Programmed cell death in neurodevelopment. Dev. Cell 32,478–490 (2015)