title: The synaptic targeting of mGluR1 by its carboxyl-terminal domain is crucial for cerebellar function.
abstract: The metabotropic glutamate receptor subtype 1 (mGluR1, Grm1) in cerebellar Purkinje cells (PCs) is essential for motor coordination and motor learning. At the synaptic level, mGluR1 has a critical role in long-term synaptic depression (LTD) at parallel fiber (PF)-PC synapses, and in developmental elimination of climbing fiber (CF)-PC synapses. mGluR1a, a predominant splice variant in PCs, has a long carboxyl (C)-terminal domain that interacts with Homer scaffolding proteins. Cerebellar roles of the C-terminal domain at both synaptic and behavior levels remain poorly understood. To address this question, we introduced a short variant, mGluR1b, which lacks this domain into PCs of mGluR1-knock-out (KO) mice (mGluR1b-rescue mice). In mGluR1b-rescue mice, mGluR1b showed dispersed perisynaptic distribution in PC spines. Importantly, mGluR1b-rescue mice exhibited impairments in inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca(2+) release, CF synapse elimination, LTD induction, and delay eyeblink conditioning: they showed normal transient receptor potential canonical (TRPC) currents and normal motor coordination. In contrast, PC-specific rescue of mGluR1a restored all cerebellar defects of mGluR1-KO mice. We conclude that the long C-terminal domain of mGluR1a is required for the proper perisynaptic targeting of mGluR1, IP3R-mediated Ca(2+) release, CF synapse elimination, LTD, and motor learning, but not for TRPC currents and motor coordination.
authors: Division of Molecular Genetics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan, Department of Physiology, School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan, PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan, Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan, Laboratory for Neural Information Technology, Graduate School of Sciences and Engineering, University of Toyama, Toyama 930-8555, Japan, Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan, Department of Anatomy, Kitasato University School of Medicine, Sagamihara 252-0374, Japan, Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies, Shizuoka 411-8540, Japan, and Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors: Yoshiaki
authors: Y
authors: Ohtani
authors: Mariko
authors: M
authors: Miyata
authors: Kouichi
authors: K
authors: Hashimoto
authors: Toshihide
authors: T
authors: Tabata
authors: Yasushi
authors: Y
authors: Kishimoto
authors: Masahiro
authors: M
authors: Fukaya
authors: Daisuke
authors: D
authors: Kase
authors: Hidetoshi
authors: H
authors: Kassai
authors: Kazuki
authors: K
authors: Nakao
authors: Tatsumi
authors: T
authors: Hirata
authors: Masahiko
authors: M
authors: Watanabe
authors: Masanobu
authors: M
authors: Kano
authors: Atsu
authors: A
authors: Aiba
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D011597:Psychomotor Performance / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1
keywords: LTD; Purkinje cells; cerebellum; eyeblink conditioning; mGluR1; synapse elimination