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

Nat Commun. 2020 Apr 14;11(1):1797. doi: 10.1038/s41467-020-15530-3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / metabolism*
  • Behavior, Animal*
  • Calcium-Binding Proteins / metabolism
  • Cell Movement
  • Female
  • Gene Expression Profiling
  • Genotype
  • Homeostasis
  • Male
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Microglia / metabolism*
  • Neurons / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phagocytosis
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / ultrastructure
  • Protein Biosynthesis*
  • Social Behavior
  • Synapses / metabolism


  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • PTEN Phosphohydrolase