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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Mutations in negative translation regulators are linked to autism spectrum disorders (ASD), predominantly affecting males.
• The specific brain cells responsible for ASD-associated elevated protein synthesis remain unidentified.

Purpose of the Study:

• To investigate the role of specific brain cells in mediating autism-like behaviors through increased protein synthesis.
• To identify the cellular mechanisms underlying the sex bias observed in autism spectrum disorders.

Main Methods:

• Conditional overexpression of the translation initiation factor eIF4E in specific brain cell types (microglia, neurons, astrocytes) in mice.
• Behavioral analysis of mice exhibiting autism-like phenotypes.
• Assessment of microglial density, morphology, phagocytic capacity, and synapse engulfment.
• Analysis of cortical neuron synapse density, neuroligin expression, and excitation-to-inhibition ratio.

Main Results:

• Exaggerated translation in microglia, but not neurons or astrocytes, induced autism-like behaviors in male mice.
• Microglial eIF4E overexpression increased microglial density and size in males, shifting them to an enhanced phagocytic, less motile state.
• Male mice exhibited increased cortical synapse density, neuroligins, and excitation-to-inhibition ratio.

Conclusions:

• Functional perturbation of male microglia, leading to altered synapse pruning, is a significant contributor to sex-biased autism spectrum disorders.
• Microglia, rather than neurons or astrocytes, are the critical cell type mediating these autism-like behaviors.
• This research highlights a novel cellular mechanism and potential therapeutic target for sex-specific ASD interventions.