2. Academic Validation
  3. The synaptic targeting of mGluR1 by its carboxyl-terminal domain is crucial for cerebellar function

The synaptic targeting of mGluR1 by its carboxyl-terminal domain is crucial for cerebellar function

  • J Neurosci. 2014 Feb 12;34(7):2702-12. doi: 10.1523/JNEUROSCI.3542-13.2014.
Yoshiaki Ohtani 1,  Mariko Miyata,  Kouichi Hashimoto,  Toshihide Tabata,  Yasushi Kishimoto,  Masahiro Fukaya,  Daisuke Kase,  Hidetoshi Kassai,  Kazuki Nakao,  Tatsumi Hirata,  Masahiko Watanabe,  Masanobu Kano,  Atsu Aiba
Affiliations

Affiliation

  • 1 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.
PMID: 24523559 DOI: 10.1523/JNEUROSCI.3542-13.2014
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.

Keywords

LTD; Purkinje cells; cerebellum; eyeblink conditioning; mGluR1; synapse elimination.

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