Transient microglial absence assists postmigratory cortical neurons in proper differentiation. Mus musculus

In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Microglia, despite their extensive surveying activity, temporarily disappear from the midembryonic CP. However, the mechanism and significance of this absence are unknown. Here, we show that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and subventricular zone and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-grown CP neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that "sanctuarization" from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.在发育中的大脑皮层内，迁移后神经元会聚集于皮层板（cortical plate, CP）中，以完成恰当分化并巩固自身的亚型身份。小胶质细胞（microglia）尽管具备广泛的脑组织监测活性，却会暂时从胚胎中期皮层板中消失。然而，该消失现象的潜在机制与生物学意义迄今仍未明确。本研究发现，小胶质细胞可通过响应脑膜与室下区释放的趋化因子CXCL12的趋化作用，发生双向迁移，进而离开胚胎中期皮层板。当在体内或体外对年轻迁移后神经元及体外培养的皮层板神经元施加非生理性的小胶质细胞过量暴露时，这些神经元会出现分化异常，表现为亚型相关转录因子及参与神经元功能成熟的基因表达紊乱。值得注意的是，该异常效应主要由小胶质细胞分泌的白细胞介素6（interleukin 6）与I型干扰素（type I interferon）所介导。本研究结果表明，胚胎中期皮层板中的神经元需要处于“免受小胶质细胞侵扰的庇护状态”（sanctuarization），才能恰当微调参与正常分化的分子表达，进而保障功能性大脑皮层环路的正常建立。