Microglia brainization: Intrinsic and environmental cues controlling developmental microglia maturation

Microglia, unlike other brain cells, do not originate from the neuroectodermal layer but migrate from the yolk sac at early embryonic stages. After seeding of microglial progenitors, they colonize the brain parenchyma and mature to become efficient brain phagocytes displaying numerous functions. However, the mechanisms that govern microglial maturation are poorly understood. We hypothesize that microglia maturation program is led by a combination of genetic intrinsic factors and environmental cues. To test our hypothesis, we focused on neuronal-related cues including neuronal scaffolding, secreted factors, and neuronal activity. First, we explored the influence of the emerging neuronal circuits by focusing on reelin, a protein involved in the scaffolding used for migration of neuronal progenitors. We found altered microglia density and distribution at P7 in the hippocampus and cerebellum, suggesting that microglia use similar migration highways as neuroprogenitors. Then, we focused on neuronal secreted factors that could regulate microglial maturation such as IL-34, a key regulator on microglial proliferation and maintenance. We found a strong reduction on microglial density in the hippocampus but not in the cerebellum of P14 IL-34 KO mice, suggesting regional differences on microglia development. Finally, to explore the influence of neuronal activity on microglial maturation we analyzed models of autism spectrum disorders (Cntnap2 KO mice) and developmental epilepsy, by intraventricular injection of kainic acid at early postnatal stages (P2, P4). Elucidating the regulators of microglial developmental milestones will provide a better understanding of neurodevelopmental disorders and the impact of early alterations on microglial maturation.