• Microglia refine thalamocortical synapses in the developing primary visual cortex • Astrocyte-secreted Hevin directly regulates microglial gene expression • Hevin engages microglial TLR4 to induce a pro-phagocytic microglial state • TLR4 is required for thalamocortical synapse refinement by microglia Microglia refine thalamocortical synapses in the developing primary visual cortex Astrocyte-secreted Hevin directly regulates microglial gene expression Hevin engages microglial TLR4 to induce a pro-phagocytic microglial state TLR4 is required for thalamocortical synapse refinement by microglia Synapse formation and elimination are two crucial processes that occur concurrently in the developing brain. Astrocytes and microglia control both processes, yet how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination is unknown. Astrocytes secrete the synaptogenic protein Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Here, we found that, in addition to this synaptogenic function, Hevin directly signals to microglia by interacting with Toll-like receptor 4 (TLR4). This signaling occurs when Hevin is proteolytically cleaved, producing a C-terminal fragment that is no longer synaptogenic. We found that Hevin, through TLR4, induces a distinct microglial state defined by increased TLR2 expression and phago-lysosomal content in vitro and in vivo . Microglial TLR4 signaling is required for the proper elimination of thalamocortical synapses during early postnatal development.
Ramírez et al. (Sun,) studied this question.