Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2.
The delta2 glutamate receptor (GluRdelta2) is predominantly expressed in Purkinje cells and plays crucial roles in cerebellar functions: GluRdelta2-/- 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 GluRdelta2-/- Purkinje cells. Recently, we demonstrated that abrogated LTD was restored in GluRdelta2-/- Purkinje cells by the virus-mediated expression of the wild-type GluRdelta2 transgene (Tg(wt)) but not by that of mutant GluRdelta2 lacking the C-terminal seven residues to which several PDZ proteins bind (Tg(DeltaCT7)). These results indicated that the C terminus of GluRdelta2 conveys the signal(s) necessary for LTD. In contrast, other phenotypes of GluRdelta2-/- 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 GluRdelta2 in vivo, we generated transgenic mice that expressed Tg(DeltaCT7) on a GluRdelta2-/- background. Interestingly, although Tg(DeltaCT7) restored abnormal PF and CF synapse formation almost completely, it could not rescue abrogated LTD in GluRdelta2-/- Purkinje cells. Furthermore, although the gross motor discoordination of GluRdelta2-/- 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 GluRdelta2, whereas other functions may be differentially regulated by other regions of GluRdelta2.
Kakegawa
Wataru
W
Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Miyazaki
Taisuke
T
Emi
Kyoichi
K
Matsuda
Keiko
K
Kohda
Kazuhisa
K
Motohashi
Junko
J
Mishina
Masayoshi
M
Kawahara
Shigenori
S
Watanabe
Masahiko
M
Yuzaki
Michisuke
M
D000818:Animals; D002531:Cerebellum / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D007858:Learning / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D054731:PDZ Domains / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D017470:Receptors, Glutamate / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2