Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRδ2
Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRδ2
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DOI：
10.1523/jneurosci.2553-07.2008
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发表时间：
2008-02-06
影响因子：
5.3
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
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作者：
Kakegawa, Wataru;Miyazaki, Taisuke;Yuzaki, Michisuke
Glu-2谷氨酸受体(Glur-2)主要表达于浦肯野细胞，在小脑功能中起关键作用：Glur-2(-/-)小鼠表现为共济失调和运动学习障碍。此外，在Glur Delta 2(-/-)浦肯野细胞中，平行纤维(PF)-浦肯野细胞突触的长时抑制(LTD)被取消，与PFS和攀升纤维(CFs)的突触形成受到严重干扰。最近，我们证明了在Glur Delta 2(-/-)Purkinje细胞中，通过病毒介导的野生型Glur Delta 2转基因基因(Tgwt)的表达可以恢复取消的LTD，但不能通过缺乏几种PDZ蛋白结合的C末端7个残基的突变体Glur Delta 2(Tg(Delta CT7))恢复。这些结果表明，GluR Delta 2的C末端传递了LTD所需的信号(S)。相反，Glur delta2(-/-)小脑的其他表型，特别是PF和CF突触的形态异常，不能通过病毒介导的瞬时表达来挽救。因此，这些表型是否由相同的信号通路介导仍不清楚。为了解决这些问题并进一步描述GluR Delta 2在体内的功能，我们产生了在Glur Delta 2(-/-)背景下表达TG(Delta CT7)的转基因小鼠。有趣的是，尽管TG(Delta CT7)几乎完全恢复了异常的PF和CF突触的形成，但它并不能挽救Glur Delta 2(-/-)浦肯野细胞中被破坏的LTD。此外，尽管Glur Delta 2(-/-)小鼠的粗大运动失调得到恢复，但延迟眨眼条件下的小脑运动学习仍然受损。这些结果表明，LTD诱导和运动学习是通过GluR Delta 2的C末端信号来调节的，而其他功能可能受GluR Delta 2的其他区域的差异调节。
The delta 2 glutamate receptor (GluR delta 2) is predominantly expressed in Purkinje cells and plays crucial roles in cerebellar functions: GluR delta 2(-/-) mice display ataxia and impaired motor learning. In addition, long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is abrogated, and synapse formation with PFs and climbing fibers (CFs) is severely disturbed in GluR delta 2(-/-) Purkinje cells. Recently, we demonstrated that abrogated LTD was restored in GluR delta 2(-/-) Purkinje cells by the virus-mediated expression of the wild-type GluR delta 2 transgene (Tgwt) but not by that of mutant GluR delta 2 lacking the C-terminal seven residues to which several PDZ proteins bind (Tg(Delta CT7)). These results indicated that the C terminus of GluR delta 2 conveys the signal(s) necessary for LTD. In contrast, other phenotypes of GluR delta 2(-/-) cerebellum, especially morphological abnormalities at PF and CF synapses, could not be rescued by virus-mediated transient expression. Thus, whether these phenotypes are mediated by the same signaling pathway remains unclear. To address these issues and to further delineate the function of GluR delta 2 in vivo, we generated transgenic mice that expressed Tg(Delta CT7) on a GluR delta 2(-/-) background. Interestingly, although Tg(Delta CT7) restored abnormal PF and CF synapse formation almost completely, it could not rescue abrogated LTD in GluR Delta 2(-/-) Purkinje cells. Furthermore, although the gross motor discoordination of GluR Delta 2(-/-) mice was restored, the cerebellar motor learning underlying delayed eyeblink conditioning remained impaired. These results indicate that LTD induction and motor learning are regulated by signaling via the C-terminal end of GluR delta 2, whereas other functions may be differentially regulated by other regions of GluR delta 2.