Sex differences in somatosensory circuitry are programmed by developmental microglia-astrocyte interaction

Men possess a greater density of cortical synapses in the adult brain relative to women, but the underlying mechanism and functional significance of this sex difference is unclear. Here, we identify a greater density of excitatory synapses in the male mouse somatosensory cortex (S1) which emerges during development and persists into the adult brain. We show that increased phagocytic activity in microglia of female mice causes a greater engulfment of astrocytes in the female S1 in a MERTK-dependent manner during a discrete developmental window, regulated at least in part by estrogen signaling. The resulting greater astrocyte density in males corresponds with an increase in astrocyte-derived synaptogenic factors, hevin and thrombospondin-2, which we propose leads to the observed sex difference in S1 synapse density. Moreover, we demonstrate that this sex difference in synapse density correlates with an increase in neuronal activity in the male S1 both in development and adulthood.