Innate immune molecules direct microglia-mediated developmental synaptic refinement
Contributors: Stevens, Beth; Greenberg, Michael E.; Gu, Chenghua; Stiles, Charles D.; Freeman, Marc R.; Schwarz, Thomas L.; Benowitz, Larry I.
Published: 2014
Language: eng
Description: Microglia, the brain's resident immune cells and phagocytes, are emerging as critical regulators of developing synaptic circuits in the healthy brain after having long been thought to function primarily during central nervous system (CNS) injury or disease. Recent work indicates that microglia engulf synapses in the developing brain; however, how microglia know which synapses to target for removal remains a major open question. For my dissertation research, I studied microglia-mediated pruning in the retinogeniculate system and sought to identify the molecules regulating microglial engulfment of synaptic inputs. I discovered that "eat me" and "don't eat me" signals, immune molecules known for either promoting or inhibiting macrophage phagocytosis of cells or debris, localize to the dorsal lateral geniculate nucleus of the thalamus (dLGN) and direct retinogeniculate refinement. 

 We found that "eat me" signal C3 and its microglial receptor, CR3, are required for normal engulfment, and that loss of either of these molecules leads to a reduction in phagocytosis and sustained deficits in refinement. These data suggest that microglia-mediated pruning may be analogous to the removal of non-self material by phagocytes in the immune system. To test this hypothesis, I examined whether protective signals are required to prevent excess microglial engulfment, as they prevent phagocytosis of self cells in the immune system. I found that protective "don't eat me" signal CD47 is required to prevent excess microglial engulfment and retinogeniculate pruning during development. Moreover, another "don't eat me signal", CD200, also prevents overpruning. 

 Together, these findings indicate that immune molecules instruct microglia as to which synapses to engulf and present a model in which a balance of stimulatory and inhibitory cues is necessary to guide remodeling of immature synaptic circuits. These data shed new light on mechanisms regulating synaptic refinement and microglial function in the healthy, developing CNS, and may have implications for disorders characterized by immune dysregulation and circuit disconnectivity, such as autism spectrum disorder (ASD) and schizophrenia.
Notes: Keywords: "don't eat me", "eat me", engulfment, microglia, refinement.

Thesis Ph.D. Harvard University 2014