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The Journal of Neuroscience, October 31, 2007, 27(44):12096-12108; doi:10.1523/JNEUROSCI.2680-07.2007

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Development/Plasticity/Repair
Regulation of Long-Term Depression and Climbing Fiber Territory by Glutamate Receptor 2 at Parallel Fiber Synapses through its C-Terminal Domain in Cerebellar Purkinje Cells

Takeshi Uemura,¹ Sho Kakizawa,² Miwako Yamasaki,³ Kenji Sakimura,⁴ Masahiko Watanabe,³ Masamitsu Iino,² and Masayoshi Mishina¹

Departments of ¹Molecular Neurobiology and Pharmacology and ²Molecular and Cellular Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ³Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, and ⁴Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan

Correspondence should be addressed to Dr. Masayoshi Mishina, Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan. Email: mishina{at}m.u-tokyo.ac.jp

Glutamate receptor (GluR) 2 selectively expressed in cerebellar Purkinje cells (PCs) plays key roles in long-term depression (LTD) induction at parallel fiber (PF)–PC synapses, motor learning, the matching and connection of PF–PC synapses in developing and adult cerebella, the elimination of multiple climbing fibers (CFs) during development, and the regulation of CF territory on PCs. However, it remains unsolved how GluR2 regulates cerebellar synaptic plasticity, PF–PC synapse formation, and CF wiring. One possible signaling mechanism through GluR2 is signaling by protein–protein interactions. The C-terminal region of GluR2 contains at least three domains for protein–protein interactions. The PDZ (postsynaptic density-95/Discs large/zona occludens 1)-binding domain at the C terminal, named as the T site, interacts with several postsynaptic density proteins. Here, we generated GluR2T mice carrying mutant GluR2 lacking the T site. There were no significant differences in the amount of receptor proteins at synapses, histological features, and the fine structures of PF–PC synapses between wild-type and GluR2T mice. However, LTD induction at PF–PC synapses and improvement in the accelerating rotarod test were impaired in GluR2T mice. Furthermore, CF territory expanded distally and ectopic innervation of CFs occurred at distal dendrites in GluR2T mice, but the elimination of surplus CF innervation at proximal dendrites appeared to proceed normally. These results suggest that the C-terminal T site of GluR2 is essential for LTD induction and the regulation of CF territory but is dispensable for PF–PC synapse formation and the elimination of surplus CFs at proximal dendrites during development.

Key words: cerebellum; climbing fiber territory; glutamate receptor 2; long-term depression; parallel fiber synapse; PDZ-binding domain

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Received June 13, 2007; revised Sept. 7, 2007; accepted Sept. 17, 2007.

Correspondence should be addressed to Dr. Masayoshi Mishina, Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan. Email: mishina{at}m.u-tokyo.ac.jp

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