Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations

Zhi-Xiang Xu, Gyu Hyun Kim, Ji-Wei Tan, Anna E. Riso, Ye Sun, Ethan Y. Xu, Guey-Ying Liao, Haifei Xu, Sang-Hoon Lee, Na-Young Do, Chan Hee Lee, Amy E. Clipperton-Allen, Soonwook Kwon, Damon T. Page, Kea Joo Lee and Baoji Xu ()
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Zhi-Xiang Xu: The Scripps Research Institute Florida
Gyu Hyun Kim: Korea Brain Research Institute
Ji-Wei Tan: The Scripps Research Institute Florida
Anna E. Riso: The Scripps Research Institute Florida
Ye Sun: Florida Atlantic University
Ethan Y. Xu: The Scripps Research Institute Florida
Guey-Ying Liao: The Scripps Research Institute Florida
Haifei Xu: The Scripps Research Institute Florida
Sang-Hoon Lee: Korea Brain Research Institute
Na-Young Do: Korea Brain Research Institute
Chan Hee Lee: Korea Brain Research Institute
Amy E. Clipperton-Allen: The Scripps Research Institute Florida
Soonwook Kwon: Catholic University of Daegu
Damon T. Page: The Scripps Research Institute Florida
Kea Joo Lee: Korea Brain Research Institute
Baoji Xu: The Scripps Research Institute Florida

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.

Date: 2020
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DOI: 10.1038/s41467-020-15530-3

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