PDF(Pubmed)
Abstract：
Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an astrocyte-secreted inhibitory synaptogenic protein. After secretion from astrocytes, neurocan is cleaved into N- and C-terminal fragments. We found that these fragments have distinct localizations in the extracellular matrix. The neurocan C-terminal fragment localizes to synapses and controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic domain have reduced inhibitory synapse numbers and function. Through super-resolution microscopy, in vivo proximity labeling by secreted TurboID, and astrocyte-specific rescue approaches, we discovered that the synaptogenic domain of neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain.
摘要：
星形胶质细胞通过分泌蛋白强烈促进突触的形成和成熟。确定了几种星形胶质细胞分泌的控制兴奋性突触发育的突触蛋白；然而，那些诱导抑制性突触发生的仍然难以捉摸。这里,我们将neurocan鉴定为星形胶质细胞分泌的抑制性突触蛋白.从星形胶质细胞分泌后，Neurocan被切割成N端和C端片段。我们发现这些片段在细胞外基质中具有不同的定位。神经囊C末端片段定位于突触并控制皮质抑制性突触的形成和功能。Neurocan敲除小鼠缺乏完整蛋白或仅其C末端突触发生结构域具有减少的抑制性突触数量和功能。通过超分辨率显微镜，通过分泌的TurboID进行体内邻近标记，和星形胶质细胞特异性救援方法，我们发现，神经的突触域可以定位于生长抑素阳性抑制性突触，并强烈调节其形成。一起,我们的研究结果揭示了星形胶质细胞控制哺乳动物脑中电路特异性抑制性突触发育的机制.
