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Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes

Authors

  • Stephan Niemann,

    1. RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    2. Cecil B. Day Laboratory for Neuromuscular Research
    3. Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
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    • *

      Current address: Epigenomics AG, Kleine Präsidentenstraße 1, 10178 Berlin, Federal Republic of Germany.

    • §

      S.N. and H.K. contributed equally to this paper.

  • Hiroaki Kanki,

    1. Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
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    • Current address: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

  • Yasuyuki Fukui,

    1. Genetic Engineering and Functional Genomics Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
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  • Keizo Takao,

    1. Genetic Engineering and Functional Genomics Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
    2. Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
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  • Masahiro Fukaya,

    1. Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
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  • Meri N. Hynynen,

    1. Cecil B. Day Laboratory for Neuromuscular Research
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  • Michael J. Churchill,

    1. RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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    • Current address: Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI 48109-1043, USA

  • Jeremy M. Shefner,

    1. Department of Neurology, Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA
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  • Roderick T. Bronson,

    1. Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
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  • Robert H. Brown Jr.,

    1. Cecil B. Day Laboratory for Neuromuscular Research
    2. Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
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  • Masahiko Watanabe,

    1. Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
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  • Tsuyoshi Miyakawa,

    1. Genetic Engineering and Functional Genomics Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
    2. Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
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  • Shigeyoshi Itohara,

    1. Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
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  • Yasunori Hayashi

    1. RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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Dr Stephan Niemann, at *Current address below.
E-mail: niste@mit.eduorniemann.stephan@gmail.com
or: Yasunori Hayashi, as above.
E-mail: yhayashi@mit.edu

Abstract

NR3B is a modulatory subunit of the NMDA receptor, abundantly expressed in both cranial and spinal somatic motoneurons and at lower levels in other regions of the brain as well. Recently, we found the human NR3B gene (GRIN3B) to be highly genetically heterogeneous, and that ∼ 10% of the normal European-American population lacks NR3B due to homozygous occurrence of a null allele in the gene. Therefore, it is especially important to understand the phenotypic consequences of the genetic loss of NR3B in both humans and animal models. We here provide results of behavioral analysis of mice genetically lacking NR3B, which is an ideal animal model due to homogeneity in genetic and environmental background. The NR3B–/– mice are viable and fertile. Consistent with the expression of NR3B in somatic motoneurons, the NR3B–/– mice showed a moderate but significant impairment in motor learning or coordination, and decreased activity in their home cages. Remarkably, the NR3B–/– mice showed a highly increased social interaction with their familiar cage mates in their home cage but moderately increased anxiety-like behaviour and decreased social interaction in a novel environment, consistent with the inhibitory role of NR3B on the functions of NMDA receptors. This work is the first reporting of the functional significance of NR3B in vivo and may give insight into the contribution of genetic variability of NR3B in the phenotypic heterogeneity among human population.

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