Journal Article

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

Vainchtein, Ilia D., Dorman, Leah C., Molofsky, Ari B., Akil, Omar, Molofsky, Anna V., Liddelow, Shane A., Nakao-Inoue, Hiromi, Chin, Gregory, Miller, John G., Cho, Frances S., Joshita, Satoru, Paz, Jeanne T., Barres, Ben A., Chien, Elliott C., Kelley, Kevin W., Nguyen, Phi T.

2018

Overview

The developing brain initially makes more synapses than it needs. With further development, excess synapses are pruned away, leaving mature circuits. Synapses can be eliminated by microglia, which engulf and destroy them. Vainchtein et al. found that the microglia are called into action by astrocytes, supportive cells on which neurons rely. Astrocytes near a redundant synapse release the cytokine interleukin-33 (IL-33), which recruits microglia to the site. In mice, disruptions in this process, as caused by deficiency in IL-33, led to too many excitatory synapses and overactive brain circuitry. Science , this issue p. 1269 Astrocytes use microglia to prune redundant neuronal synapses. 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.

• Publisher: The American Association for the Advancement of Science
• Subject: 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