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

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.

Our results indicate that elevated neuronal protein synthesis does not lead to deficits in social interaction, but it produces some ASD-related behaviors. NN4E mice of both sexes displayed elevated anxiety, a common ASD comorbidities. In addition, as revealed by marble burying tests, elevated neuronal protein synthesis increased repetitive behavior in female but not male mice. These behavioral phenotypes are interesting, given the observation that elevated microglial protein synthesis impaired social behaviors without elevating anxiety in male mice. These results indicate that different ASD-like and related behaviors have distinct cellular basis. They also suggest that ASD manifestations could be different in females and males.

https://www.nature.com/articles/s41467-020-15530-3

https://www.neurologia.com//noticia/7705/relacion-entre-autismo-masculino-y-sobreexpresion-de-celulas-microgliales

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