The N-Terminal Domain of GluD2 (GluRδ2) Recruits Presynaptic Terminals and Regulates Synaptogenesis in the Cerebellum In Vivo
The N-Terminal Domain of GluD2 (GluRδ2) Recruits Presynaptic Terminals and Regulates Synaptogenesis in the Cerebellum In Vivo
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DOI：
10.1523/jneurosci.6013-08.2009
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发表时间：
2009-05-06
影响因子：
5.3
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
--
作者：
Kakegawa, Wataru;Miyazaki, Taisuke;Yuzaki, Michisuke
δ 2谷氨酸受体（GluR δ 2; GluD 2）主要表达于小脑中平行纤维（PF）-浦肯野细胞突触的突触后位点，在小脑中起着两个关键作用：PF突触的形成和长时程抑制（LTD）的调节，LTD是运动学习基础上的突触可塑性形式。虽然LTD和运动学习的诱导绝对需要通过GluD 2的胞质C-末端结构域的信号传导，但GluD 2调节PF突触发生的机制仍不清楚。在这里，我们研究的作用，细胞外N-末端结构域（NTD）的GluD 2 PF突触通过注射辛德毕斯病毒携带野生型（GluD 2（wt））或突变型GluD 2到蛛网膜下腔小脑上空间的GluD 2-null小鼠。值得注意的是，GluD 2（wt）的表达，而不是缺乏NTD的突变型GluD 2（GluD 2（Delta NTD））的表达，迅速诱导PF突触形成，并在注射后仅1天的成年GluD 2缺失小鼠中挽救了粗大运动失调。此外，虽然红藻氨酸受体GluR 6（GluK 2）不诱导PF突触发生，但含有GluD 2的NTD的嵌合GluK 2（GluD 2（NTD）-GluK 2）诱导。类似地，GluD 2（wt）和GluD 2（NTD）-GluK 2，而不是GluD 2（Delta NTD），在体外诱导异源细胞中的突触发生。相反，LTD恢复在GluD 2-null浦肯野细胞表达的突变体GluD 2缺乏NTD。这些结果表明GluD 2的NTD对于GluD 2调节PF -浦肯野细胞突触发生的功能是必要和充分的。此外，我们的研究结果表明，GluD 2不同的调节PF突触和小脑LTD通过细胞外的NTD和细胞质的C-末端，分别。
The delta 2 glutamate receptor (GluR delta 2; GluD2), which is predominantly expressed on postsynaptic sites at parallel fiber (PF)-Purkinje cell synapses in the cerebellum, plays two crucial roles in the cerebellum: the formation of PF synapses and the regulation of long-term depression (LTD), a form of synaptic plasticity underlying motor learning. Although the induction of LTD and motor learning absolutely require signaling via the cytoplasmic C-terminal domain of GluD2, the mechanisms by which GluD2 regulates PF synaptogenesis have remained unclear. Here, we examined the role of the extracellular N-terminal domain (NTD) of GluD2 on PF synaptogenesis by injecting Sindbis virus carrying wild-type (GluD2(wt)) or mutant GluD2 into the subarachnoid supracerebellar space of GluD2-null mice. Remarkably, the expression of GluD2(wt), but not of a mutant GluD2 lacking the NTD (GluD2(Delta NTD)), rapidly induced PF synapse formation and rescued gross motor dyscoordination in adult GluD2-null mice just 1 d after injection. In addition, although the kainate receptor GluR6 (GluK2) did not induce PF synaptogenesis, a chimeric GluK2 that contained the NTD of GluD2 (GluD2(NTD)-GluK2) did. Similarly, GluD2(wt) and GluD2(NTD)-GluK2, but not GluD2(Delta NTD), induced synaptogenesis in heterologous cells in vitro. In contrast, LTD was restored in GluD2-null Purkinje cells expressing a mutant GluD2 lacking the NTD. These results indicate that the NTD of GluD2 is necessary and sufficient for the function of GluD2 in the regulation of PF -Purkinje cell synaptogenesis. Furthermore, our results suggest that GluD2 differently regulates PF synaptogenesis and cerebellar LTD through the extracellular NTD and the cytoplasmic C-terminal end, respectively.