Sexual dimorphism of complement-dependent microglial synaptic pruning and other immune pathways in the developing brain

Sexual dimorphism has been reported in the prevalence, onset and progression of neurodevelopmental and neurodegenerative disorders. We hypothesize that immunological signaling in the developing brain, notably the complement cascade underlying microglial synaptic pruning, could be one mechanism for this dimorphism. Here we show that genes differentially expressed between male and female normal cortical development are enriched for pathways associated with the activation of the innate immune system, complement cascade and phagocytic processes. Specifically, the male brain is enriched for the expression of genes associated with phagocytic function of microglia through complement-dependent synaptic pruning especially at the developmental stages before birth. Our results suggest the existence of a common regulatory module involved in both prenatal immune activation in males and postnatal immune activation in females. The activation of immune pruning pathways at different stages of normal male and female development could provide valuable insights about critical periods of plasticity and refinement in the human cortex that could explain the different vulnerabilities of males and females to neurological disorders.