The Journal of Neuroscience, February 6, 2008, 28(6):1460-1468; doi:10.1523/JNEUROSCI.2553-07.2008
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Cellular/Molecular
Differential Regulation of Synaptic Plasticity and Cerebellar Motor Learning by the C-Terminal PDZ-Binding Motif of GluR
2
Wataru Kakegawa,1
Taisuke Miyazaki,2
Kyoichi Emi,1
Keiko Matsuda,1
Kazuhisa Kohda,1
Junko Motohashi,1
Masayoshi Mishina,3
Shigenori Kawahara,4
Masahiko Watanabe,2 and
Michisuke Yuzaki1
1Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan, 2Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, 3Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, and 4Laboratory of Neurobiophysics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan
Correspondence should be addressed to Michisuke Yuzaki, Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: myuzaki{at}sc.itc.keio.ac.jp
The 
2 glutamate receptor (GluR2) is predominantly expressed in Purkinje cells and plays crucial roles in cerebellar functions: GluR2–/– 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 GluR2–/– Purkinje cells. Recently, we demonstrated that abrogated LTD was restored in GluR2–/– Purkinje cells by the virus-mediated expression of the wild-type GluR2 transgene (Tgwt) but not by that of mutant GluR2 lacking the C-terminal seven residues to which several PDZ proteins bind (Tg
CT7). These results indicated that the C terminus of GluR2 conveys the signal(s) necessary for LTD. In contrast, other phenotypes of GluR2–/– 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 GluR2 in vivo, we generated transgenic mice that expressed TgCT7 on a GluR2–/– background. Interestingly, although TgCT7 restored abnormal PF and CF synapse formation almost completely, it could not rescue abrogated LTD in GluR2–/– Purkinje cells. Furthermore, although the gross motor discoordination of GluR2–/– 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 GluR2, whereas other functions may be differentially regulated by other regions of GluR2.
Key words: cerebellum; LTD; glutamate receptor; PDZ domains; Purkinje cell; eyeblink
Received June 6, 2007;
revised Dec. 14, 2007;
accepted Dec. 16, 2007.
Correspondence should be addressed to Michisuke Yuzaki, Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: myuzaki{at}sc.itc.keio.ac.jp
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W. Kakegawa, T. Miyazaki, K. Kohda, K. Matsuda, K. Emi, J. Motohashi, M. Watanabe, and M. Yuzaki
The N-Terminal Domain of GluD2 (GluR{delta}2) Recruits Presynaptic Terminals and Regulates Synaptogenesis in the Cerebellum In Vivo
J. Neurosci.,
May 6, 2009;
29(18):
5738 - 5748.
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