mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination.

Targeted deletion of metabotropic glutamate receptor-subtype 1 (mGluR1) gene can cause defects in development and function in the cerebellum. We introduced the mGluR1alpha transgene into mGluR1-null mutant [mGluR1 (-/-)] mice with a Purkinje cell (PC)-specific promoter. mGluR1-rescue mice showed normal cerebellar long-term depression and regression of multiple climbing fiber innervation, events significantly impaired in mGluR1 (-/-) mice. The impaired motor coordination was rescued by this transgene, in a dose-dependent manner. We propose that mGluR1 in PCs is a key molecule for normal synapse formation, synaptic plasticity, and motor control in the cerebellum.

[1]  S. Tonegawa,et al.  Impaired synapse elimination during cerebellar development in PKCγ mutant mice , 1995, Cell.

[2]  Youngnam Kang,et al.  Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice , 1995, Cell.

[3]  S. Nakanishi,et al.  Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. , 1994, The Journal of biological chemistry.

[4]  Shigetada Nakanishi,et al.  Metabotropic glutamate receptors: Synaptic transmission, modulation, and plasticity , 1994, Neuron.

[5]  P. Somogyi,et al.  Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone , 1996, Nature.

[6]  S. Zackson,et al.  A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. , 1990, Science.

[7]  G. Collingridge,et al.  Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1 , 1994, Nature.

[8]  S. Tonegawa,et al.  Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice , 1994, Cell.

[9]  S. Nakanishi,et al.  Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. , 2000, The New England journal of medicine.

[10]  S. Nakanishi,et al.  Sequence and expression of a metabotropic glutamate receptor , 1991, Nature.

[11]  H. Daniel,et al.  Incomplete regression of multiple climbing fibre innervation of cerebellar Purkinje cells in mGluR1 mutant mice , 1997, Neuroreport.

[12]  A. Konnerth,et al.  Synaptic‐ and agonist‐induced excitatory currents of Purkinje cells in rat cerebellar slices. , 1991, The Journal of physiology.

[13]  M. Kano,et al.  Phospholipase cbeta4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  E. Mugnaini,et al.  Dynamic organization of developing Purkinje cells revealed by transgene expression. , 1991, Science.

[15]  S. Nakanishi.  Molecular diversity of glutamate receptors and implications for brain function. , 1992, Science.

[16]  S. Tonegawa,et al.  Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice , 1994, Cell.

[17]  Elimination of Functional Synapses During Development of the Nervous System , 1987 .

[18]  Effect of cerebellum injuries on movement coordination in running dogs , 1966 .

[19]  F. Crépel.  Regression of functional synapses in the immature mammalian cerebellum , 1982, Trends in Neurosciences.

[20]  J. Changeux,et al.  A theory of the epigenesis of neuronal networks by selective stabilization of synapses. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Bao,et al.  Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  Susumu Tonegawa,et al.  Persistent Multiple Climbing Fiber Innervationof Cerebellar Purkinje Cellsin Mice Lacking mGluR1 , 1997, Neuron.

[23]  Richard J Smeyne,et al.  Local Control of Granule Cell Generation by Cerebellar Purkinje Cells , 1995, Molecular and Cellular Neuroscience.

[24]  Richard F. Thompson,et al.  Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Galphaq. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Udo,et al.  Cerebellar control of locomotion: effects of cooling cerebellar intermediate cortex in high decerebrate and awake walking cats. , 1980, Journal of neurophysiology.