Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development

Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the in...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 359; no. 6381; pp. 1269 - 1273
Main Authors:	Vainchtein, Ilia D, Chin, Gregory, Cho, Frances S, Kelley, Kevin W, Miller, John G, Chien, Elliott C, Liddelow, Shane A, Nguyen, Phi T, Nakao-Inoue, Hiromi, Dorman, Leah C, Akil, Omar, Joshita, Satoru, Barres, Ben A, Paz, Jeanne T, Molofsky, Ari B, Molofsky, Anna V
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 16-03-2018
Subjects:	Anatomy Animals Astrocytes Astrocytes - metabolism Brain Central nervous system Central Nervous System - growth & development Central Nervous System - metabolism Circuits Cytokines Homeostasis Interleukin 1 Interleukin-33 - genetics Interleukin-33 - metabolism Mice Mice, Knockout Microglia Microglia - physiology Nerve Net - growth & development Neurodevelopmental disorders Neurogenesis Sensorimotor Cortex - growth & development Sensorimotor Cortex - physiology Spinal cord Synapses Synapses - physiology Synaptogenesis Thalamus Thalamus - abnormalities
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Summary:	Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the interleukin-1 family cytokine interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors contributions: I.D.V., G.C., A.V.M, and J.G.M. designed, performed and analyzed most experiments. E.C.C., H.N-I, P.T.N., and L.C.D. contributed to experiments and data analysis. F.S.C and J.T.P. designed, performed and analyzed the electrophysiology experiments. K.W.K and I.D.V designed and performed bioinformatics analyses. S.A.L. performed and analyzed culture experiments under supervision of B.A.B. O.A. performed and analyzed auditory testing. S.J. generated Il33-H2B-mCherry mice. A.V.M and A.B.M designed experiments and wrote the manuscript together with I.D.V., G.C. and other authors.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.aal3589