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Down-regulation of metabotropic glutamate receptor 1α in globus pallidus and substantia nigra of parkinsonian monkeys

Authors

  • K. Kaneda,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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    • *

      K.K. and Y.T. contributed equally to this work.

  • 1,2,3, Y. Tachibana,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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    • *

      K.K. and Y.T. contributed equally to this work.

  • 4, M. Imanishi,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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  • 1 H. Kita,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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  • 3 R. Shigemoto,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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  • 5 A. Nambu,

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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  • and 4 M. Takada 1

    1. 1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo 183-8526, Japan
      2 The Japan Society for the Promotion of Science, Tokyo 102-8471, Japan
      3 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, College of Medicine, Memphis, TN 38163, USA
      Divisions of 4System Neurophysiology and 5Cerebral Structure, National Institute for Physiological Sciences and School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
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Dr M. Takada, 1Tokyo Metropolitan Institute for Neuroscience, as above.
E-mail: takada@tmin.ac.jp

Abstract

Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1α, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1-related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1-related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down-regulation of pallidal and nigral mGluR1α in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus-derived glutamatergic input that is generated in the disease.

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