Circadian rhythms in microglia mediate early life synaptic development in a sex-specific manner.

Adolescence is a critical window when synaptic connectivity is refined, in part by microglia that engulf synaptic elements. Here, in adolescent mice, we show that hippocampal microglia exhibit diurnal transcriptional rhythms, with synaptic pruning gene expression peaking during the rest phase.

Inducible deletion of the core clock gene Bmal1 in microglia abolishes these rhythms and alters developing hippocampal synapses in a sex-dependent manner. In males, clock disruption increases synapse engulfment, reduces dendritic spine density, and decreases synaptic connectivity; females show similar reductions in synaptic connectivity without overt postsynaptic structural changes. Microglial clock disruption also induces broad, sex-specific changes in synapse-related gene expression that overlap with neurodevelopmental disorder pathways and lead to impaired memory and sociability, indicating microglial clocks as key regulators of developmental synapse refinement.