Trans-Synaptic Interaction of GluRδ2 and Neurexin through Cbln1 Mediates Synapse Formation in the Cerebellum
Trans-Synaptic Interaction of GluRδ2 and Neurexin through Cbln1 Mediates Synapse Formation in the Cerebellum
复制标题
DOI：
10.1016/j.cell.2010.04.035
复制
发表时间：
2010-06-11
期刊：
影响因子：
64.5
通讯作者：
Mishina, Masayoshi
中科院分区：
文献类型：
--
作者：
Uemura, Takeshi;Lee, Sung-Jin;Mishina, Masayoshi
阐明调节突触形成的分子机制是理解神经连接、高级大脑功能和精神障碍所必需的。尽管有丰富的体外信息，但关于哺乳动物大脑中谷氨酸能突触是如何形成的基本问题仍然没有答案。谷氨酸受体(Glur)β2是体内小脑突触形成所必需的。在这里，我们证明了GluR Delta 2的N-末端结构域(NTD)通过小脑蛋白1前体蛋白(Cbln1)与突触前神经毒素(NRXns)相互作用。在Cbln1基因敲除小鼠的小脑原代培养中，Glur Delta 2的突触生成活性被取消，并通过重组Cbln1恢复。GluR Delta 2的NTD和NRXN1β的胞外区都抑制了Cbln1在原代培养和体内的突触生成活性。这些结果表明，GluR delta2通过Cbln1与突触前NRXN相互作用，从而介导小脑突触的形成。
Elucidation of molecular mechanisms that regulate synapse formation is required for the understanding of neural wiring, higher brain functions, and mental disorders. Despite the wealth of in vitro information, fundamental questions about how glutamatergic synapses are formed in the mammalian brain remain unanswered. Glutamate receptor (GluR) delta 2 is essential for cerebellar synapse formation in vivo. Here, we show that the N-terminal domain (NTD) of GluR delta 2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). The synaptogenic activity of GluR delta 2 is abolished in cerebellar primary cultures from Cbln1 knockout mice and is restored by recombinant Cbln1. Knockdown of NRXNs in cerebellar granule cells also hinders the synaptogenic activity of GluR delta 2. Both the NTD of GluR delta 2 and the extracellular domain of NRXN1 beta suppressed the synaptogenic activity of Cbln1 in cerebellar primary cultures and in vivo. These results suggest that GluR delta 2 mediates cerebellar synapse formation by interacting with presynaptic NRXNs through Cbln1.