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

Zhi-Xiang Xu,Anna E Riso,Amy E Clipperton-Allen,Ethan Y Xu,Damon T Page,Baoji Xu,Ji-Wei Tan,Kea Joo Lee,Ye Sun,Sang-Hoon Lee,Haifei Xu,Chan Hee Lee,Soonwook Kwon,Guey-Ying Liao,Na-Young Do,Gyu Hyun Kim

doi:10.1038/s41467-020-15530-3

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.

Highlights

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
Fragile X syndrome is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP)[14], and the mammalian target of rapamycin complex 1 (mTORC1)-eIF4E pathway is over-activated in fragile X syndrome patients diagnosed with ASD15
As it is generally believed that elevated protein synthesis in neurons causes ASD-like behaviors[27], we first overexpressed eIF4E in neurons by crossing R26Eif4e mice with Syn1-Cre mice, which selectively express Cre in neurons as early as embryonic day 12.529, to generate Syn1-Cre;R26Eif4e/Eif4e mice (Fig. 1a)

Summary

Introduction

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. Fragile X syndrome is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP)[14], and the mTORC1-eIF4E pathway is over-activated in fragile X syndrome patients diagnosed with ASD15. These single-gene disorders account for over 3% of all ASD cases[3]. Coding Eif4ebp[2] gene or overexpression of eIF4E under the promoter of beta tubulin (βT-Eif4e) increases protein synthesis in the mouse brain and leads to ASD-like behaviors[16,17]

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Results

Conclusion