All Title Author
Keywords Abstract

PLOS ONE  2008 

MGluR5 Mediates the Interaction between Late-LTP, Network Activity, and Learning

DOI: 10.1371/journal.pone.0002155

Full-Text   Cite this paper   Add to My Lib


Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5–10 Hz) and gamma (30–100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.


[1]  Bear MF (1996) A synaptic basis for memory storage in the cerebral cortex. Proc Natl Acad Sci U S A 93: 13453–13459.
[2]  Kemp A, Manahan-Vaughan D (2007a) Hippocampal long-term depression: master or minion in declarative memory processes? Trends Neurosci 30: 111–118.
[3]  Manahan-Vaughan D (1997) Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats. J Neurosci 17: 3303–3311.
[4]  Manahan-Vaughan D, Braunewell KH (1999) Novelty acquisition is associated with induction of hippocampal long-term depression. Proc Natl Acad Sci U S A 96: 8739–8744.
[5]  Abraham WC (2003) How long will long-term potentiation last? Philos Trans R Soc Lond B Biol Sci 358: 735–744.
[6]  Cohen AS, Abraham WC (1996) Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors. J Neurophysiol 76: 953–962.
[7]  Cohen AS, Raymond CR, Abraham WC (1998) Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C. Hippocampus 8: 160–170.
[8]  H?lscher C, Anwyl R, Rowan MJ (1997) Activation of group-II metabotropic glutamate receptors blocks induction of long-term potentiation and depotentiation in area CA1 of the rat in vivo. Eur J Pharmacol 322: 155–163.
[9]  Wilsch VW, Behnisch T, Jager T, Reymann KG, Balschun D (1998) When are class I metabotropic glutamate receptors necessary for long-term potentiation? J Neurosci 18: 6071–6080.
[10]  Balschun D, Manahan-Vaughan D, Wagner T, Behnisch T, Reymann KG, et al. (1999) A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning. Learn Mem 6: 138–152.
[11]  Naie K, Manahan-Vaughan D (2004) Regulation by metabotropic glutamate receptor 5 of LTP in the dentate gyrus of freely moving rats: relevance for learning and memory formation. Cereb Cortex 14: 189–198.
[12]  Hermans E, Challiss RA (2001) Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359: 465–484.
[13]  Gasparini F, Kuhn R, Pin J-P (2002) Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr Opin Pharmacol 2: 43–49.
[14]  Conn PJ, Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37: 205–237.
[15]  Cummings JA, Mulkey RM, Nicoll RA, Malenka RC (1996) Ca2+ signaling requirements for long-term depression in the hippocampus. Neuron 16: 825–833.
[16]  Frey U, Frey S, Schollmeier F, Krug M (1996) Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro. J Physiol 490: 703–711.
[17]  Manahan-Vaughan D, Kulla A, Frey JU (2000) Requirement of translation but not transcription for the maintenance of long-term depression in the CA1 region of freely moving rats. J Neurosci 20: 8572–8576.
[18]  Manahan-Vaughan D, Braunewell KH (2005) The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cereb Cortex 15: 1703–1713.
[19]  Manahan-Vaughan D, Ngomba RT, Storto M, Kulla A, Catania MV, et al. (2003) An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats. Neuropharmacol 44: 17–25.
[20]  Whittington MA, Traub RD, Jefferys JGR (1995) Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373: 612–615.
[21]  Cobb SR, Bulters DO, Davies CH (2000) Coincident activation of mGluRs and mAChRs imposes theta frequency patterning on synchronised network activity in the hippocampal CA3 region. Neuropharmacol 39: 1933–1942.
[22]  Traub RD, Pais I, Bibbig A, Lebeau FE, Buhl EH, et al. (2005) Transient depression of excitatory synapses on interneurons contributes to epileptiform bursts during gamma oscillations in the mouse hippocampal slice. J Neurophysiol 94: 1225–1235.
[23]  Gasparini F, Lingerh?hl K, Stoehr N, Flor PJ, Heinrich M, et al. (1999) 2-methyl-6-(phenylethyl)-pyridine (MPEP), a potent, selective and systematically active mGluR5 receptor antagonist. Neuropharmacol 38: 1493–1503.
[24]  Casabona G, Knopfel T, Kuhn R, Gasparini F, Baumann P, et al. (1997) Expression and coupling to polyphosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain. Eur J Neurosci 9: 12–17.
[25]  Knoflach F, Mutel V, Jolidon S, Kew JNC, Malherbe P, et al. (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action and binding site. Proc Natl Acad Sci U S A 98: 13402–13407.
[26]  Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, et al. (2006) A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. Mol Pharmacol 70: 616–626.
[27]  Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, et al. (2007) Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol Pharmacol 71: 1389–1398.
[28]  Lisman JE, Otmakhova NA (2001) Storage, recall, and novelty detection of sequences by the hippocampus: elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine. Hippocampus 11: 551–568.
[29]  Bragin A, Jando G, Nadasdy Z, Hetke J, Wise K, et al. (1995) Gamma (40-–100 Hz) oscillation in the hippocampus of the behaving rat. J Neurosci 15: 47–60.
[30]  Kocsis B, Bragin A, Buzsáki G (1999) Interdependence of multiple theta generators in the hippocampus: a partial coherence analysis. J Neurosci 19: 6200–6212.
[31]  Csicsvari J, Jamieson B, Wise KD, Buzsáki G (2003) Mechanisms of gamma oscillations in the hippocampus of the behaving rat. Neuron 37: 311–322.
[32]  Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, et al. (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 17: 5196–5205.
[33]  Balschun D, Zuschratter W, Wetzel W (2006) Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory. Neurosci 142: 691–702.
[34]  Uzakov S, Frey JU, Korz V (2005) Reinforcement of rat hippocampal LTP by holeboard training. Learn Mem 12: 165–171.
[35]  Kemp A, Manahan-Vaughan D (2007b) The Hippocampal CA1 region and dentate gyrus differentiate between environmental and spatial feature encoding through long-term depression. Cereb Cortex. In press..
[36]  Barnes CA, Jung MW, McNaughton BL, Korol DL, Andreasson K, et al. (1994) LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci 14: 5793–5806.
[37]  Moser EI, Krobert KA, Moser MB, Morris RG (1998) Impaired spatial learning after saturation of long-term potentiation. Science 281: 2038–2042.
[38]  Moser EI, Moser MB (1999) Is learning blocked by saturation of synaptic weights in the hippocampus? Neurosci Biobehav Rev 23: 661–672.
[39]  Cain DP, Hargreaves EL, Boon F, Dennison Z (1993) An examination of the relations between hippocampal long-term potentiation, kindling, afterdischarge, and place learning in the water maze. Hippocampus 3: 153–163.
[40]  Chinestra P, Aniksztejn L, Diabira D, Ben-Ari Y (1993) (RS)-alpha-methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons. J Neurophysiol 70: 2684–2689.
[41]  Manzoni OJ, Weisskopf MG, Nicoll RA (1994) MCPG antagonizes metabotropic glutamate receptors but not long-term potentiation in the hippocampus. Eur J Neurosci 6: 1050–1054.
[42]  Thomas MJ, O'Dell TJ (1995) The molecular switch hypothesis fails to explain the inconsistent effects of the metabotropic glutamate receptor antagonist MCPG on long-term potentiation. Brain Res 695: 45–52.
[43]  Selig DK, Lee HK, Bear MF, Malenka RC (1995) Reexamination of the effects of MCPG on hippocampal LTP, LTD, and depotentiation. J Neurophysiol 74: 1075–1082.
[44]  Fitzjohn SM, Palmer MJ, May JER, Neeson A, Morris SAC, et al. (2001) A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro. J Physiol 537: 421–430.
[45]  Manahan-Vaughan D, Braunewell KH, Reymann KG (1998) Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats. Neurosci 86: 709–721.
[46]  Neyman S, Manahan-Vaughan D (2008) Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro. Eur J Neurosci. 27: 1345–1352.
[47]  Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci 21: 5925–5934.
[48]  Braunewell KH, Brackmann M, Manahan-Vaughan D (2003) Group I mGlu receptors regulate the expression of the neuronal calcium sensor protein VILIP-1 in vitro and in vivo: implications for mGlu receptor-dependent hippocampal plasticity? Neuropharmacol 44: 707–715.
[49]  Huber KM, Roder JC, Bear MF (2001) Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol 86: 321–325.
[50]  Chrobak JJ, Buzsáki G (1998) Gamma oscillations in the entorhinal cortex of the freely behaving rat. J Neurosci 18: 388–398.
[51]  Buzsáki G (2002) Theta oscillations in the hippocampus. Neuron 33: 325–340.
[52]  Buzsáki G (2005) Theta rhythm of navigation: link between path integration and landmark navigation, episodic and semantic memory. Hippocampus 15: 827–840.
[53]  Axmacher N, Mormann F, Fernandez G, Elger CE, Fell J (2006) Memory formation by neuronal synchronization. Brain Res Rev 52: 170–82.
[54]  Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8: 45–56.
[55]  Sourdet V, Russier M, Daoudal G, Ankri N, Debanne D (2003) Long-term enhancement of neuronal excitability and temporal fidelity mediated by metabotropic glutamate receptor subtype 5. J Neurosci 23: 10238–10248.
[56]  Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF, et al. (1994) Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79: 365–375.
[57]  Bordi F, Reggiani A, Conquet F (1997) Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice. Brain Res 761: 121–126.
[58]  Hughes SW, Lorincz M, Cope DW, Blethyn KL, Kekesi KA, et al. (2004) Synchronized oscillations at alpha and theta frequencies in the lateral geniculate nucleus. Neuron 42: 253–268.
[59]  Hughes SW, Cope DW, Blethyn KL, Crunelli V (2002) Cellular mechanisms of the slow (<1 Hz) oscillation in thalamocortical neurons in vitro. Neuron 33: 947–958.
[60]  Lanneau C, Harries MH, Ray AM, Cobb SR, Randall A, et al. (2002) Complex interactions between mGluR1 and mGluR5 shape neuronal network activity in the rat hippocampus. Neuropharmacol 43: 131–140.
[61]  Thuault SJ, Davies CH, Randall AD, Collingridentate gyruse GL (2002) Group I mGluRs modulate the pattern of non-synaptic epileptiform activity in the hippocampus. Neuropharmacol 43: 141–146.
[62]  Ben-Ari Y, Gho M (1988) Long-lasting modification of the synaptic properties of rat CA3 hippocampal neurones induced by kainic acid. J Physiol 404: 365–384.
[63]  Nakajima S, Franck JE, Bilkey D, Schwartzkroin PA (1991) Local circuit synaptic interactions between CA1 pyramidal cells and interneurons in the kainate-lesioned hyperexcitable hippocampus. Hippocampus 1: 67–78.
[64]  Queiroz CM, Mello LE (2007) Synaptic plasticity of the CA3 commissural projection in epileptic rats: an in vivo electrophysiological study. Eur J Neurosci 2007 25: 3071–3079.
[65]  Cozzi A, Meli E, Carla V, Pellicciari R, Moroni F, et al. (2002) Metabotropic glutamate 1 (mGlu1) receptor antagonists enhance GABAergic neurotransmission: a mechanism for the attenuation of post-ischemic injury and epileptiform activity? Neuropharmacol 43: 119–130.
[66]  Naie K, Manahan-Vaughan D (2005) Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-D-aspartate and metabotropic glutamate receptor-dependent mechanisms. Eur J Neurosci 21: 411–421.
[67]  Kulla A, Manahan-Vaughan D (2000) Depotentiation in the dentate gyrus of freely moving rats is modulated by D1/D5 dopamine receptors. Cereb Cortex 10: 614–620.
[68]  Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press.
[69]  Dunwiddie T, Lynch G (1978) Long-term potentiation and depression of synaptic responses in the rat hippocampus: localization and frequency dependency. J Physiol 276: 353–367.
[70]  Frey U, Krug M, Reymann KG, Matthies H (1988) Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res 452: 57–65.


comments powered by Disqus