Tyrosine Phosphatases Regulate AMPA Receptor Trafficking during Metabotropic Glutamate Receptor-Mediated Long-Term Depression

Two forms of long-term depression (LTD), triggered by activation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), respectively, can be induced at CA1 synapses in the hippocampus. Compared with NMDAR-LTD, relatively little is known about mGluR-LTD. Here, we show that protein tyrosine phosphatase (PTP) inhibitors, orthovanadate and phenylarsine oxide, selectively block mGluR-LTD induced by application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD), because NMDAR-LTD is unaffected by these inhibitors. Furthermore, DHPG-LTD measured using whole-cell recording is similarly blocked by either bath-applied or patch-loaded PTP inhibitors. These inhibitors also block the changes in paired-pulse facilitation and coefficient of variation that are associated with the expression of DHPG-LTD. DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate. Finally, in dissociated hippocampal neurons, orthovanadate blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites. Again, the effects of PTP blockade were selective, because NMDA-induced decreases in surface AMPAR clusters was unaffected by orthovanadate. Together, these data suggest that activation of postsynaptic PTP results in tyrosine dephosphorylation of AMPARs and their removal from the synapse.

[1]  S. Siegelbaum,et al.  Postsynaptic induction and presynaptic expression of hippocampal long-term depression. , 1994, Science.

[2]  S. Siegelbaum,et al.  Altered Presynaptic Vesicle Release and Cycling during mGluR-Dependent LTD , 2002, Neuron.

[3]  M. Bear,et al.  Chemical induction of mGluR5- and protein synthesis--dependent long-term depression in hippocampal area CA1. , 2001, Journal of neurophysiology.

[4]  G. Collingridge,et al.  Developmental Changes in Synaptic AMPA and NMDA Receptor Distribution and AMPA Receptor Subunit Composition in Living Hippocampal Neurons , 2000, The Journal of Neuroscience.

[5]  G. Collingridge,et al.  Removal of AMPA Receptors (AMPARs) from Synapses Is Preceded by Transient Endocytosis of Extrasynaptic AMPARs , 2004, The Journal of Neuroscience.

[6]  K. M. Huber,et al.  Developmental Switch in Synaptic Mechanisms of Hippocampal Metabotropic Glutamate Receptor-Dependent Long-Term Depression , 2005, The Journal of Neuroscience.

[7]  David Lodge,et al.  DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists , 1999, Neuropharmacology.

[8]  Mark von Zastrow,et al.  Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD , 2000, Nature Neuroscience.

[9]  Roger A. Nicoll,et al.  Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors , 2001, Neuropharmacology.

[10]  M. Bear,et al.  Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  I. Kilpatrick,et al.  Protein phosphatase inhibitors facilitate DHPG‐induced LTD in the CA1 region of the hippocampus , 2001, British journal of pharmacology.

[12]  Mark F. Bear,et al.  Internalization of ionotropic glutamate receptors in response to mGluR activation , 2001, Nature Neuroscience.

[13]  D. Kullmann.  Amplitude fluctuations of , 1994, Neuron.

[14]  R. Malenka,et al.  Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus , 1992, Neuron.

[15]  Mark F Bear,et al.  NMDA Induces Long-Term Synaptic Depression and Dephosphorylation of the GluR1 Subunit of AMPA Receptors in Hippocampus , 1998, Neuron.

[16]  G. Collingridge,et al.  An investigation of depotentiation of longterm potentiation in the CA1 region of the hippocampus , 2007, Experimental Brain Research.

[17]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[18]  M. Bear,et al.  Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1 , 2004, The Journal of Neuroscience.

[19]  G. Collingridge,et al.  NSF Binding to GluR2 Regulates Synaptic Transmission , 1998, Neuron.

[20]  G. R. Seabrook,et al.  The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus , 1997, Neuropharmacology.

[21]  M. Bear,et al.  Long-term depression in hippocampus. , 1996, Annual review of neuroscience.

[22]  Jacques Noël,et al.  Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes , 2001, Neuropharmacology.

[23]  R. Nicoll,et al.  Contribution of cytoskeleton to the internalization of AMPA receptors. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Nicoll,et al.  Two Distinct Forms of Long-Term Depression Coexist in CA1 Hippocampal Pyramidal Cells , 1997, Neuron.

[25]  Hans-Ulrich Dodt,et al.  Activation of mGlu receptors induces LTD without affecting postsynaptic sensitivity of CA1 neurons in rat hippocampal slices , 2003, The Journal of physiology.

[26]  S. Siegelbaum,et al.  12-Lipoxygenase Metabolites of Arachidonic Acid Mediate Metabotropic Glutamate Receptor-Dependent Long-Term Depression at Hippocampal CA3-CA1 Synapses , 2003, The Journal of Neuroscience.

[27]  Graham L. Collingridge,et al.  The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events , 2001, Journal of Neuroscience Methods.

[28]  P. Somogyi,et al.  Biochemical and immunocytochemical characterization of antipeptide antibodies to a cloned GluR1 glutamate receptor subunit: Cellular and subcellular distribution in the rat forebrain , 1993, Neuroscience.

[29]  G. Collingridge,et al.  Tyrosine dephosphorylation underlies DHPG-induced LTD , 2002, Neuropharmacology.

[30]  Andreas Lüthi,et al.  Hippocampal LTD Expression Involves a Pool of AMPARs Regulated by the NSF–GluR2 Interaction , 1999, Neuron.

[31]  A. M. Watabe,et al.  Postsynaptic induction and presynaptic expression of group 1 mGluR-dependent LTD in the hippocampal CA1 region. , 2002, Journal of neurophysiology.

[32]  D. Ogden,et al.  Evidence for Protein Tyrosine Phosphatase, Tyrosine Kinase, and G-Protein Regulation of the Parallel Fiber Metabotropic Slow EPSC of Rat Cerebellar Purkinje Neurons , 2003, The Journal of Neuroscience.

[33]  G. Collingridge,et al.  Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus. , 1993, European journal of pharmacology.

[34]  M. Bear,et al.  Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. , 2000, Science.

[35]  W. Abraham,et al.  Tyrosine phosphorylation-dependent inhibition of hippocampal synaptic plasticity , 2000, Neuropharmacology.

[36]  M. W. Brown,et al.  A quantitative study of the actions of excitatory amino acids and antagonists in rat hippocampal slices , 1988, British journal of pharmacology.

[37]  D. Carpenter,et al.  The Mechanism of Presynaptic Long-Term Depression Mediated by Group I Metabotropic Glutamate Receptors , 2003, Cellular and Molecular Neurobiology.

[38]  M. Sheng,et al.  Tyrosine phosphorylation of GluR2 is required for insulin‐stimulated AMPA receptor endocytosis and LTD , 2004, The EMBO journal.

[39]  K. Hsu,et al.  Rap1-induced p38 Mitogen-activated Protein Kinase Activation Facilitates AMPA Receptor Trafficking via the GDI·Rab5 Complex , 2004, Journal of Biological Chemistry.

[40]  W. Abraham,et al.  Metabotropic glutamate receptor-mediated depression of the slow afterhyperpolarization is gated by tyrosine phosphatases in hippocampal CA1 pyramidal neurons. , 2004, Journal of neurophysiology.

[41]  R. Nicoll,et al.  Endocannabinoids contribute to short‐term but not long‐term mGluR‐induced depression in the hippocampus , 2003, The European journal of neuroscience.

[42]  G. Collingridge,et al.  A characterisation of long‐term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro , 2001, The Journal of physiology.