Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRδ2

被引:59
作者
Kakegawa, Wataru [1 ]
Miyazaki, Taisuke [2 ]
Emi, Kyoichi [1 ]
Matsuda, Keiko [1 ]
Kohda, Kazuhisa [1 ]
Motohashi, Junko [1 ]
Mishina, Masayoshi [3 ]
Kawahara, Shigenori [4 ]
Watanabe, Masahiko [2 ]
Yuzaki, Michisuke [1 ]
机构
[1] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan
[2] Hokkaido Univ, Dept Anat, Grad Sch Med, Sapporo, Hokkaido 0608638, Japan
[3] Univ Tokyo, Dept Mol Neurobiol & Pharmacol, Grad Sch Med, Tokyo 1130033, Japan
[4] Univ Tokyo, Lab Neurobiophys, Grad Sch Pharmaceut Sci, Tokyo 1130033, Japan
关键词
cerebellum; LTD; glutamate receptor; PDZ domains; Purkinje cell; eyeblink;
D O I
10.1523/JNEUROSCI.2553-07.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1460 / 1468
页数:9
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