Nature. How does a fever relieve autism?

As early as 1990, it was reported that bacterial infection and subsequent inflammation were beneficial to the relief of neurodevelopmental disorders.for example, some children with autism spectrum disorder (ASD) have a temporary but significant improvement in autism symptoms after high fever [2,3].ASD is caused by both external environmental factors and internal genetic factors [4].at present, several commonly used ASD mouse models often carry mutations of high-risk ASD genes such as cntnap2 [5], FMR1 [6] and Shank3 [7], respectively, and show symptoms of abnormal behavior and social laziness [8, 9].of course, this phenomenon also exists in the ASD mouse model caused by external environmental factors such as maternal and fetal inflammation [10].however, whether at the molecular level or at the nervous system level, how the inflammatory immune response characterized by high fever is related to neurodevelopmental disorders is still an unsolved mystery.on December 19, 2019, Gloria B. Choi from MIT and Jun R. huh from Harvard University published the title IL-17A promoters society in mouse models of neurodevelopmental in nature In the paper of disorders, we found that IL-17A, a cytokine produced in the inflammatory reaction, can directly affect the neural activity in the brain, thus alleviating the social behavior disorders in mice to a certain extent.firstly, two mouse models were established.one is the high fever model of mice. The mice were intraperitoneally injected with low-dose LPS. After 4-5 hours, the body temperature of the mice increased significantly.the other is the ASD model induced by the maternal fetal immune response (MIA), that is, the female mice on the 12th day of pregnancy (E12.5) were injected with pol yinosinic:polycytidylic acid(referred to as poly I: C), the immune response of the mother mice, then, the subsequent born mice will appear the phenomenon of social disorder (hereinafter referred to as MIA mice).the authors found that compared with the control mice, Mia mice injected with LPS had obvious social tendency.however, in ASD models induced by mutations of cntnap2, FMR1 or Shank3, LPS injection did not alleviate social disorder.that is to say, the inflammatory reaction induced by LPS can specifically alleviate the social disorder induced by MIA in mice to a certain extent.previous work of the authors pointed out that the main physiological abnormalities of MIA mice occurred in the primary somatosensory cortex dystrophic zone (s1dz).specifically, the author found that the neurons in this region of MIA mice were highly activated through FOS staining of neural cell activation label; moreover, reducing the level of s1dz nerve activation can alleviate the social disorder of mice [11].therefore, the authors next investigated whether LPS also affected the neural activation level of s1dz. the authors found that compared with the control mice, the level of s1dz nerve activation in MIA mice injected with LPS was significantly decreased and decreased to the level of normal mice. therefore, LPS alleviates the social disorder of MIA mice and decreases the activation level of s1dz. LPS can induce the production and secretion of a series of inflammatory factors [12]. the authors found that the levels of IFN - γ, IL-6, IL-17A and TNF were significantly increased in mice injected with LPS. moreover, s1dz neurons expressed IL-17A receptor IL7RA. next, the authors injected the neutralizing antibody of IL-17A into the brain of MIA mice, and found that after antagonizing the effect of IL-17A, LPS "alleviated the social disorder of MIA mice" and "decreased the activation level of s1dz" basically disappeared. finally, the authors also found that LPS had no effect on s1dz neuron specific il17ra deficient mice. these results indicate that the inflammatory factor IL-17A induced by LPS can alleviate the social disorder of MIA mice by acting on the nerve cells of s1dz. to sum up, the authors established the relationship between inflammation and social disorder at the tissue and molecular levels through the high fever inflammation model induced by LPS and ASD model induced by MIA in mice. first of all, the authors found two phenomena: at the behavioral level, LPS can alleviate the social disorder of MIA mice; at the histological level, LPS can reduce the level of s1dz nerve activation in mice. however, previous work of the authors indicated that lowering the level of s1dz nerve activation can alleviate the social disorder of MIA mice. therefore, the author concluded that "LPS alleviates social disorder in MIA mice by reducing the activation level of s1dz. secondly, the molecular mechanism was discussed. LPS can induce and promote the expression and secretion of a series of inflammatory factors including IL-17A. the author confirmed the key role of IL-17A, that is, antagonizing IL-17A, and the effect of LPS previously found disappeared. therefore, the authors propose a model of inflammation relieving ASD: LPS induces IL-17A, and IL-17A acts on IL-17A receptor il17ra in s1dz nerve cells, and reduces the activation level of s1dz nerve cells induced by MIA, thus alleviating ASD. In recent years, there have been a number of articles published by people who have been working in China for a long time, with a number of references 1. White, M. wagner-jaureggand peer therapy. Med. Hist. 34, 294 – 310 (1990). 2. Curran, L.K. et al. Behaviors associated with fever in children with audit spectrum disorders. Pediatrics 120, e1386 – e1392 (2007). 3. Grzadzzinski, R., Lord, C., Sanders, S.J., weling, D. & amp & amp; amp; amp; amp; amp; amp; P, zinski, R., R., Lord, C., Sanders, S.J., weling, D. & amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; amp; D, a; BAL, V H. Children with autism spectrum disorder who improve with fever: insights from the Simons Simplex Collection. Autism Res. 11, 175–184 (2018).4. Lyall, K. et al. The changing epidemiology of autism spectrum disorders. Annu. Rev. Public Health 38, 81–102 (2017).5. Peñagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).6. The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78, 23–33 (1994).7. Peça, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).8. Crawley, J. N. Translational animal models of autism and neurodevelopmental disorders. Dialogues Clin. Neurosci. 14, 293–305 (2012).9. Ey, E., Leblond, C. S. & Bourgeron, T. Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 4, 5–16 (2011).10. Patterson, P. H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011).11. Yim, Y. et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549, 482–487 (2017).12. Erickson, M. A. & Banks, W. A. Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav. Immun. 25, 1637–1648 (2011).