Postnatal downregulation of Fmr1 in microglia promotes microglial reactivity and causes behavioural alterations in female mice.

Background: Fragile X syndrome is caused by the loss of the Fmr1 gene expression. Deletion of Fmr1 in various neuronal and non-neuronal subpopulations in the brain of mice leads to cell-type-specific effects. Microglia, immune cells critical for the refinement of neuronal circuits during brain development, have been implicated in various neurodevelopmental disorders, including fragile X syndrome. However, it is unknown whether reduced Fmr1 expression in microglia leads to molecular and behavioral phenotypes.

Methods: We downregulated Fmr1 in microglia during early and late postnatal development and studied the effect on microglial morphology and distinct behaviours.

Results: Female, but not male, adult mice with downregulation of Fmr1 in microglia during early development exhibited reactive microglia and behavioral phenotypes, including enhanced self-grooming and alterations in social interaction. Downregulation of Fmr1 in microglia during late development induced a milder phenotype, characterized by impaired preference for social novelty without affecting microglia morphology.

Conclusions: The downregulation of Fmr1 and its encoded protein FMRP in microglia contributes to behavioural phenotypes in a sex-specific manner.