The Requirement of Presynaptic Metabotropic Glutamate Receptors for the Maintenance of Locomotion

Spinal circuits known as central pattern generators maintain vertebrate locomotion. In the lamprey, the contralaterally alternating ventral root activity that defines this behavior is driven by ipsilateral glutamatergic excitation (Buchanan and Grillner, 1987) coupled with crossed glycinergic inhibition (Buchanan, 1982; Alford and Williams, 1989). These mechanisms are distributed throughout the spinal cord. Glutamatergic excitatory synapses activate AMPA and NMDA receptors known to be necessary for the maintenance of the locomotor rhythm. Less is known of the role and location of metabotropic glutamate receptors (mGluRs), although group I mGluRs enhance transmitter release at giant synapses in the lamprey spinal cord, whereas group II/III receptors may inhibit release. In this study we show that group I mGluR antagonists block fictive locomotion, a neural correlate of locomotion, by acting at the presynaptic terminal. Under physiological conditions, synaptically released glutamate activates presynaptic group I mGluRs (autoreceptors) during the repetitive activation of glutamatergic terminals. The resulting rise in [Ca2+]i caused by the release from presynaptic intracellular stores is coincident with an enhancement of synaptic transmission. Thus, blocking mGluRs reduces glutamate release during the repetitive activity that is characteristic of locomotion, leading to the arrest of locomotor activity. We found the effects of group I mGluRs on locomotion to be inconsistent with a postsynaptic effect on the central pattern generator. Consequently, the activation of metabotropic glutamate autoreceptors is necessary to maintain rhythmic motor output. Our results demonstrate the role of presynaptic mGluRs in the physiological control of movement for the first time.

[1]  Aaron M. Beedle,et al.  G Protein Modulation of N-type Calcium Channels Is Facilitated by Physical Interactions between Syntaxin 1A and Gβγ* , 2000, The Journal of Biological Chemistry.

[2]  S. Grillner,et al.  Newly identified 'glutamate interneurons' and their role in locomotion in the lamprey spinal cord. , 1987, Science.

[3]  S Grillner,et al.  Control of locomotion in vertebrates: spinal and supraspinal mechanisms. , 1988, Advances in neurology.

[4]  R. Tsien,et al.  Multiple Structural Elements in Voltage-Dependent Ca2+ Channels Support Their Inhibition by G Proteins , 1996, Neuron.

[5]  S. Grillner,et al.  Activation of NMDA receptors elecits fictive locomotion and bistable membrane properties in the lamprey spinal cord , 1985, Brain Research.

[6]  S. Grillner,et al.  5-Hydroxytryptamine depresses reticulospinal excitatory postsynaptic potentials in motoneurons of the lamprey , 1991, Neuroscience Letters.

[7]  Bertil Hille,et al.  G protein-coupled mechanisms and nervous signaling , 1992, Neuron.

[8]  L M Jordan,et al.  ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 860: 83-93 (1998) Initiation of Locomotion in Mammals , 2022 .

[9]  Simon Alford,et al.  Metabotropic Glutamate Receptor–Mediated Control of Neurotransmitter Release , 1998, Neuron.

[10]  D. Clapham,et al.  The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart , 1987, Nature.

[11]  T. Manabe,et al.  Calcium‐dependent mechanisms involved in presynaptic long‐term depression at the hippocampal mossy fibre–CA3 synapse , 1999, The European journal of neuroscience.

[12]  Simon Alford,et al.  Calcium influx‐independent depression of transmitter release by 5‐HT at lamprey spinal cord synapses , 2001, The Journal of physiology.

[13]  S. Grillner,et al.  Modeling of the Spinal Neuronal Circuitry Underlying Locomotion in a Lower Vertebratea , 1998, Annals of the New York Academy of Sciences.

[14]  R. S. Jones,et al.  Differential actions of PKA and PKC in the regulation of glutamate release by group III mGluRs in the entorhinal cortex. , 2001, Journal of neurophysiology.

[15]  S. Nakanishi,et al.  MOLECULAR DIVERSITY OF THE GLUTAMATE RECEPTORS , 1992, Clinical neuropharmacology.

[16]  G. Lombardi,et al.  Presynaptic mGlu1 type receptors potentiate transmitter output in the rat cortex. , 1998, European journal of pharmacology.

[17]  D. Budd,et al.  Protein Kinase C‐Mediated Suppression of the Presynaptic Adenosine A1 Receptor by a Facilitatory Metabotropic Glutamate Receptor , 1995, Journal of neurochemistry.

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

[19]  J. Clements,et al.  Presynaptic glutamate receptors depress excitatory monosynaptic transmission between mouse hippocampal neurones. , 1990, The Journal of physiology.

[20]  J. Kaplan,et al.  Facilitation of Synaptic Transmission by EGL-30 Gqα and EGL-8 PLCβ DAG Binding to UNC-13 Is Required to Stimulate Acetylcholine Release , 1999, Neuron.

[21]  S. Alford,et al.  Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release. , 2000, Journal of neurophysiology.

[22]  S. Grillner,et al.  N-methyl-d-aspartate (NMDA), kainate and quisqualate receptors and the generation of fictive locomotion in the lamprey spinal cord , 1985, Brain Research.

[23]  S. Grillner,et al.  Effects of metabotropic glutamate receptor activation on the cellular and network level in the lamprey spinal cord. , 1994, Neuroreport.

[24]  S. Grillner,et al.  Does the central pattern generation for locomotion in lamprey depend on glycine inhibition? , 1980, Acta physiologica Scandinavica.

[25]  L. R. Merlin.  Group I mGluR-mediated silent induction of long-lasting epileptiform discharges. , 1999, Journal of neurophysiology.

[26]  K. Mackie,et al.  Modulation of Ca2+ channels βγ G-protein py subunits , 1996, Nature.

[27]  S. Grillner,et al.  Activity-Dependent Metaplasticity of Inhibitory and Excitatory Synaptic Transmission in the Lamprey Spinal Cord Locomotor Network , 1999, The Journal of Neuroscience.

[28]  R. Duvoisin,et al.  The metabotropic glutamate receptors: Structure and functions , 1995, Neuropharmacology.

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

[30]  J. Pin,et al.  Pharmacology and functions of metabotropic glutamate receptors. , 1997, Annual review of pharmacology and toxicology.

[31]  F. Gasparini,et al.  CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. , 1999, Molecular pharmacology.

[32]  Dawei Zhang,et al.  Activation of metabotropic glutamate receptors enhances synaptic transmission at the Drosophila neuromuscular junction , 1999, Neuropharmacology.

[33]  K. Campbell,et al.  Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. , 1997, Nature.

[34]  G. Collingridge,et al.  Roles of metabotropic glutamate receptors in LTP and LTD in , 1999, Current Opinion in Neurobiology.

[35]  A. El Manira,et al.  Interaction between Metabotropic and Ionotropic Glutamate Receptors Regulates Neuronal Network Activity , 2000, The Journal of Neuroscience.

[36]  S. Alford,et al.  Glutamate receptor‐mediated synaptic excitation in axons of the lamprey. , 1997, The Journal of physiology.

[37]  S. Alford,et al.  G Protein βγ Subunit-Mediated Presynaptic Inhibition: Regulation of Exocytotic Fusion Downstream of Ca2+ Entry , 2001, Science.

[38]  P. Wallén,et al.  The neuronal correlate of locomotion in fish , 1980, Experimental Brain Research.

[39]  J. Feldman,et al.  Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons , 1996, The Journal of Neuroscience.

[40]  G. Lombardi,et al.  Pharmacological characterization of 1-aminoindan-1,5-dicarboxylic acid, a potent mGluR1 antagonist. , 1997, The Journal of pharmacology and experimental therapeutics.

[41]  G. Fischbach,et al.  Neurotransmitters decrease the calcium component of sensory neurone action potentials , 1978, Nature.

[42]  Denise S Walker,et al.  Direct binding of G-protein βλ complex to voltage-dependent calcium channels , 1997, Nature.

[43]  S. Ikeda.  Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. , 1996, Nature.

[44]  Carl W. Cotman,et al.  Micromolar L-2-amino-4-phosphonobutyric acid selectively inhibits perforant path synapses from lateral entorhinal cortex , 1981, Brain Research.

[45]  George J. Augustine,et al.  Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites , 1998, Nature.

[46]  S. Grillner,et al.  Presynaptic GABAA and GABAB Receptor‐mediated Phasic Modulation in Axons of Spinal Motor Interneurons , 1991, The European journal of neuroscience.

[47]  S. Grillner,et al.  Endogenous activation of metabotropic glutamate receptors contributes to burst frequency regulation in the lamprey locomotor network , 1998, The European journal of neuroscience.

[48]  R K Wong,et al.  Excitatory synaptic potentials dependent on metabotropic glutamate receptor activation in guinea‐pig hippocampal pyramidal cells. , 1995, The Journal of physiology.

[49]  D. Watanabe,et al.  Glutamate receptors: brain function and signal transduction 1 Published on the World Wide Web on 21 October 1997. 1 , 1998, Brain Research Reviews.

[50]  J. Burke,et al.  Presynaptic depression of synaptic transmission mediated by activation of metabotropic glutamate receptors in rat neocortex , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  Y. Jan,et al.  Activation of the cloned muscarinic potassium channel by G protein βγ subunits , 1994, Nature.

[52]  S. Alford,et al.  Endogenous activation of glycine and NMDA receptors in lamprey spinal cord during fictive locomotion , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  B. Hille,et al.  A diffusible second messenger mediates one of the pathways coupling receptors to calcium channels in rat sympathetic neurons , 1991, Neuron.

[54]  S. Grillner,et al.  N-methyl-D-aspartate receptor-induced, inherent oscillatory activity in neurons active during fictive locomotion in the lamprey , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  J. Buchanan.  Identification of interneurons with contralateral, caudal axons in the lamprey spinal cord: synaptic interactions and morphology. , 1982, Journal of neurophysiology.

[56]  Yan-Yi Peng.  Ryanodine-Sensitive Component of Calcium Transients Evoked by Nerve Firing at Presynaptic Nerve Terminals , 1996, The Journal of Neuroscience.

[57]  S. Alford,et al.  NMDA Receptor-Mediated Control of Presynaptic Calcium and Neurotransmitter Release , 1999, The Journal of Neuroscience.

[58]  E. M. Silinsky.  On the mechanism by which adenosine receptor activation inhibits the release of acetylcholine from motor nerve endings. , 1984, The Journal of physiology.

[59]  K. Mackie,et al.  Modulation of Ca2+ channels by G-protein beta gamma subunits. , 1996, Nature.

[60]  S. Ikeda.  Voltage-dependent modulation of N-type calcium channels by G-protein β γsubunits , 1996, Nature.

[61]  S. Grillner,et al.  Intrinsic function of a neuronal network — a vertebrate central pattern generator 1 Published on the World Wide Web on 8 April 1998. 1 , 1998, Brain Research Reviews.

[62]  D. Clapham,et al.  The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. , 1987, Nature.

[63]  L. R. Merlin,et al.  Role of metabotropic glutamate receptor subtypes in the patterning of epileptiform activities in vitro. , 1995, Journal of neurophysiology.

[64]  J J Jack,et al.  Assessment of the reliability of amplitude histograms from excitatory synapses in rat hippocampal CA1 In Vitro , 1997, The Journal of physiology.

[65]  Atsuko Fukunaga,et al.  A novel class of antagonists for metabotropic glutamate receptors, 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylates , 1996 .