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

Wataru Kakegawa, Taisuke Miyazaki, Kyoichi Emi, Keiko Matsuda, Kazuhisa Kohda, Junko Motohashi, Masayoshi Mishina, Shigenori Kawahara, Masahiko Watanabe, Michisuke Yuzaki

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

The δ2 glutamate receptor (GluRδ2) is predominantly expressed in Purkinje cells and plays crucial roles in cerebellar functions: GluRδ2-/- 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 GluRδ2-/- Purkinje cells. Recently, we demonstrated that abrogated LTD was restored in GluRδ2-/- Purkinje cells by the virus-mediated expression of the wild-type GluRδ2 transgene (Tgwt) but not by that of mutant GluRδ2 lacking the C-terminal seven residues to which several PDZ proteins bind (Tg ΔCT7). These results indicated that the C terminus of GluRδ2 conveys the signal(s) necessary for LTD. In contrast, other phenotypes of GluRδ2-/- 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 GluRδ2 in vivo, we generated transgenic mice that expressed TgΔCT7 on a GluRδ2-/- background. Interestingly, although TgΔCT7 restored abnormal PF and CF synapse formation almost completely, it could not rescue abrogated LTD in GluRδ2-/- Purkinje cells. Furthermore, although the gross motor discoordination of GluRδ2-/- 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 GluRδ2, whereas other functions may be differentially regulated by other regions of GluRδ2.

Original languageEnglish
Pages (from-to)1460-1468
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number6
DOIs
Publication statusPublished - 2008 Feb 6

Keywords

  • Cerebellum
  • Eyeblink
  • Glutamate receptor
  • LTD
  • PDZ domains
  • Purkinje cell

ASJC Scopus subject areas

  • Neuroscience(all)

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