Skip to main content

Group I Metabotropic Glutamate Receptors: A Role in Neurodevelopmental Disorders?

Abstract

Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are coupled to polyphosphoinositide hydrolysis and are involved in activity-dependent forms of synaptic plasticity, both during development and in the adult life. Group I mGlu receptors can also regulate proliferation, differentiation, and survival of neural stem/progenitor cells, which further support their role in brain development. An exaggerated response to activation of mGlu5 receptors may underlie synaptic dysfunction in Fragile X syndrome, the most common inherited form of mental retardation. In addition, group I mGlu receptors are overexpressed in dysplastic neurons of focal cortical dysplasia and hemimegaloencephaly, which are disorders of cortical development associated with chronic epilepsy. Drugs that block the activity of group I mGlu receptors (in particular, mGlu5 receptors) are potentially helpful for the treatment of Fragile X syndrome and perhaps other neurodevelopmental disorders.

This is a preview of subscription content, access via your institution.

References

  1. Canudas AM, Di Giorgi-Gerevini V, Iacovelli L, Nano G, D’Onofrio M, Arcella A, Giangaspero F, Busceti C, Ricci-Vitiani L, Battaglia G, Nicoletti F, Melchiorri D (2004) PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors. J Neurosci 24(46):10343–10352

    PubMed  CAS  Google Scholar 

  2. Brazel CY, Nunez JL, Yang Z, Levison SW (2005) Glutamate enhances survival and proliferation of neural progenitors derived from the subventricular zone. Neuroscience 131(1):55–65

    PubMed  CAS  Google Scholar 

  3. Cappuccio I, Spinsanti P, Porcellini A, Desiderati F, De Vita T, Storto M, Capobianco L, Battaglia G, Nicoletti F, Melchiorri D (2005) Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells. Neuropharmacology 49:196–205

    PubMed  CAS  Google Scholar 

  4. Di Giorni Gerevini VD, Caruso A, Cappuccio I, Ricci-Vitiani L, Romeo S, Della Rocca C, Gradini R, Melchiorri D, Nicoletti F (2004) The mGlu5 metabotropic glutamate receptor is expressed in zones of active neurogenesis of the embryonic and postnatal brain. Dev Brain Res 150:17–22

    Google Scholar 

  5. López-Bendito G, Shigemoto R, Fairén A, Luján R (2002) Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb Cortex 12(6):625–638

    PubMed  Google Scholar 

  6. Mienville J-M (1999) Cajal–Retzius cells physiology: just in time to bridge the 20th century. Cereb Cortex 9:776–782

    PubMed  CAS  Google Scholar 

  7. Bardoni B, Davidovic L, Bensaid M, Khandjan EW (2006) The Fragile X syndrome: exploring its molecular basis and seeking a treatment. Expert Rev Mol Med 8(8):1–16

    PubMed  Article  Google Scholar 

  8. Kniazeff J, Bessis AS, Maurel D, Ansnay H, Prézeau L, Pin J-P (2004) Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol 11(8):706–713

    PubMed  CAS  Google Scholar 

  9. Pin J-P, Kniazeff J, Liu J, Binet V, Goudet C, Rondard P, Prézeau L (2005) Allosteric functioning of dimeric class C G-protein-coupled receptors. FEBS J 272:2947–2955

    PubMed  CAS  Google Scholar 

  10. Goudet C, Kniazeff J, Hlavackova V, Malhaire F, Maurel D, Acher F, Blahos J, Prézeau L, Pin J-P (2005) Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators. J Biochem 280(26):24380–24385

    CAS  Google Scholar 

  11. Prézeau L, Gomeza J, Ahern S, Mary S, Galvez T, Bockaert J, Pin J-P (1996) Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by alternative splicing generate receptors with differing agonist-independent activity. Mol Pharmacol 49(3):422–429

    PubMed  Google Scholar 

  12. Hardingham NR, Bannister NJ, Read JC, Fox KD, Hardingham GE, Jack JJ (2006) Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors. J Neurosci 26:6337–6345

    PubMed  CAS  Google Scholar 

  13. Litschig S, Gasparini F, Rueegg D, Stoehr N, Flor PJ, Vranesic I, Prézeau L, Pin JP, Thomsen C, Kuhn R (1999) CPCCOEt, a non competitive metabotropic glutamate receptor 1 antagonist, inhibit receptor signalling without affecting glutamate binding. Mol Pharmacol 55(3):453–461

    PubMed  CAS  Google Scholar 

  14. Pagano A, Rüegg D, Litschig S, Stoehr N, Stierlin C, Heinrich M, Floersheim P, Prézeau L, Carrol F, Pin J-P, Cambria A, Vranesic I, Flor PJ, Gasparini F, Kuhn R (2000) The non competitive antagonist 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J Biol Chem 275(43):33750–33758

    PubMed  CAS  Google Scholar 

  15. Carrol FY, Stolle A, Beart PM, Voerste A, Brabet I, Mauler F, Joly C, Antonicek H, Bockaert J, Müller T, Pin J-P, Prézeau L (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol 59(5):965–973

    Google Scholar 

  16. Hermans E, Challiss RAJ (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

    PubMed  CAS  Google Scholar 

  17. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38(10):1493–1503

    PubMed  CAS  Google Scholar 

  18. Maj M, Bruno V, Dragic Z, Yananoto R, Battaglia G, Inderbitzin W, Stoehr N, Stein T, Gasparini F, Vranesic I, Kuhn R, Nicoletti F, Flor PJ (2003) (–)–PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 45:895–906

    PubMed  CAS  Google Scholar 

  19. Luján R, Roberts JD, Shigemoto R, Ohishi H, Somogyi P (1997) Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat 13:219–241

    PubMed  Google Scholar 

  20. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299(1):12–20

    PubMed  CAS  Google Scholar 

  21. Kawabata S, Tsutsumi R, Kohara A, Yamaguchi T, Nakanishi S, Okada M (1996) Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature 383:89–92

    PubMed  CAS  Google Scholar 

  22. Berridge MJ (1998) Neuronal calcium signaling. Neuron 21:13–26

    PubMed  CAS  Google Scholar 

  23. Peavy RD, Conn PJ (1998) Phosphorylation of mitogen-activated protein kinase in cultured rat cortical glia by stimulation of metabotropic glutamate receptors. J Neurochem 71(2):603–612

    PubMed  CAS  Article  Google Scholar 

  24. Ferraguti F, Baldani-Guerra B, Corsi M, Nakanishi S, Corti C (1999) Activation of the extracellular signal-regulated kinase 2 by metabotropic glutamate receptors. Eur J Neurosci 11(6):2073–2082

    PubMed  CAS  Google Scholar 

  25. Rong R, Ahn J-Y, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH, Ye K (2003) PI3Kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nature Neurosci 6(11):1153–1161

    PubMed  CAS  Google Scholar 

  26. Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ, Worley PF (1998) Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of Homer-related, synaptic proteins. Neuron 21:707–716

    PubMed  CAS  Google Scholar 

  27. Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF (1998) Homer binds a novel prolin-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21:717–726

    PubMed  CAS  Google Scholar 

  28. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density protein. Neuron 23:583–592

    PubMed  CAS  Google Scholar 

  29. Ango F, Prézeau L, Muller T, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L (2001) Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411:962–965

    PubMed  CAS  Google Scholar 

  30. Coutinho V, Kavanagh I, Sugiyama H, Tones MA, Henley JM (2001) Characterization of a metabotropic glutamate receptor type 5-green fluorescent protein chimera (mGluR5-GFP): pharmacology, surface expression, and differential effects of Homer-1a and Homer-1c. Mol Cell Neurosci 18:296–306

    PubMed  CAS  Google Scholar 

  31. Ango F, Robbe D, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L (2002) Homer-dependent cell surface expression of metabotropic glutamate receptor type 5 in neurons. Mol Cell Neurosci 20:323–329

    PubMed  CAS  Google Scholar 

  32. Sergé A, Fourgeaud L, Hémar A, Choquet D (2002) Receptor activation and Homer differentially control the lateral mobility of metabotropic glutamate receptor 5 in the neuronal membrane. J Neurosci 22(10):3910–3920

    PubMed  Google Scholar 

  33. Kammermeier PJ, Xiao B, Tu JC, Worley PF, Ikeda SR (2000) Homer proteins regulate coupling of group I metabotropic glutamate receptors to N-type calcium and M-type potassium channel. J Neurosci 20(19):7238–7245

    PubMed  CAS  Google Scholar 

  34. Mao L, Yang L, Tang Q, Samdani S, Zhang G, Wang JW (2005) The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J Neurosci 25(10):2741–2752

    PubMed  CAS  Google Scholar 

  35. Alagarsamy S, Saugstad J, Warren L, Mansuy IM, Gereau RW 4th, Conn PJ (2005) NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. Neuropharmacology 49(Suppl 1):135–145

    PubMed  CAS  Google Scholar 

  36. Catania MV, Landwehrmeywer GB, Testa CM, Standaert DG, Penney JB, Young AB (1994) Metabotropic glutamate receptors are differentially regulated during development. Neuroscience 61(3):481–495

    PubMed  CAS  Google Scholar 

  37. Minakami R, Iida K, Hirakawa N, Sugiyama H (1995) The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development. J Neurochem 65(4):1536–1542

    PubMed  CAS  Article  Google Scholar 

  38. Romano C, Van den Pol AN, O’Malley KL (1996) Enhance early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. J Comp Neurol 367:403–412

    PubMed  CAS  Google Scholar 

  39. Van den Pol AN, Romano C, Ghosh P (1995) Metabotropic glutamate receptor mGluR5 subcellular distribution and developmental expression in hypothalamus. J Comp Neurol 362(1):134–150

    PubMed  Google Scholar 

  40. Romano C, Smout S, Miller JK, O’Malley KL (2002) Developmental regulation of metabotropic glutamate receptor 5b protein in rodent brain. Neuroscience 111(3):693–698

    PubMed  CAS  Google Scholar 

  41. Casabona G, Knöpfel T, Kuhn R, Gasparini F, Baumann P, Sortino MA, Copani A, Nicoletti F (1997) Expression and coupling to polyphosphoinositide hydrolysis of group-I metabotropic glutamate receptor in early postnatal and adult rat brain. Eur J Neurosci 9(1):12–17

    PubMed  CAS  Google Scholar 

  42. Furuta A, Martin LJ (1999) Laminar segregation of the cortical plate during corticogenesis is accompanied by changes in glutamate receptor expression. J Neurobiol 39:67–80

    PubMed  CAS  Google Scholar 

  43. Petralia RS, Sans N, Wang Y-X, Wenthold RJ (2005) Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol Cell Neurosci 29(3):436–452

    PubMed  CAS  Google Scholar 

  44. Nicoletti F, Iadarola MJ, Wrobleski JT, Costa E (1986) Excitatory amino acid recognition sites coupled with inositolphospholipid metabolism: developmental changes and interaction with a1-adrenoceptor. Proc Natl Acad Sci USA 83:1931–1935

    PubMed  CAS  Google Scholar 

  45. Nicoletti F, Meek JL, Iadarola MJ, Chuang DM, Roth BL, Costa E (1986) Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J Neurochem 46(1):40–46

    PubMed  CAS  Google Scholar 

  46. Dudek SM, Bowen WD, Bear MF (1989) Postnatal changes in glutamate stimulated phosphoinositide turnover in rat neocortical synaptoneurosomes. Brain Res Dev Brain Res 47:123–128

    PubMed  CAS  Google Scholar 

  47. Schoepp DD, Johnson BG (1989) Inhibition of excitatory amino acid-stimulated phosphoinositide hydrolysis in the neonatal rat hippocampus by 2-amino-3-phosphonopropionate. J Neurochem 53(6):1865–1870

    PubMed  CAS  Google Scholar 

  48. Sortino MA, Nicoletti F, Canonico PL (1991) “Metabotropic” glutamate receptors in rat hypothalamus: characterization and developmental profile. Brain Res Dev Brain Res 61(2):169–172

    PubMed  CAS  Google Scholar 

  49. Spinsanti P, De Vita T, Di Castro S, Storto M, Formisano P, Nicoletti F, Melchiorri D (2006) Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increases in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. J Neurochem 99:299–307

    PubMed  CAS  Google Scholar 

  50. Di Giorni Gerevini VD, Melchiorri D, Battaglia G, Ricci-Vitiani L, Busceti CL, Biagioni F, Iacovelli L, Canudas AM, Parati E, De Maria R, Nicoletti F (2005) Endogenous activation of metabotrophic glutamate receptors supports the proliferation and survival of neural progenitor cells. Cell Death Differ 12(8):1124–1133

    Google Scholar 

  51. Frotscher M (1998) Cajal–Retzius cells, reelin and the formation of layers. Curr Opin Neurobiol 8:570–575

    PubMed  CAS  Google Scholar 

  52. Martínez-Galán JR, López-Bendito G, Luján R, Shigemoto R, Fairén, Valdeolmillos M (2001) Cajal–Retzius cells in early postnatal mouse cortex selectively express functional metabotropic glutamate receptors. Eur J Neurosci 13:1147–1154

    PubMed  Google Scholar 

  53. Longone P, Impagnatiello F, Giudotti A, Costa E (1997) mGluR1,5 stimulation increases REELIN mRNA expression in cultured cerebellar granule neurons (CGN). Society of Neuroscience 23(2815):52

    Google Scholar 

  54. Copani A, Bruno VM, Barresi V, Battaglia G, Condorelli DF, Nicoletti F (1995) Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture. J Neurochem 64(1):101–108

    PubMed  CAS  Article  Google Scholar 

  55. Copani A, Casabona G, Bruno V, Caruso A, Condorelli DF, Messina A, Di Giorgi–Gerevini V, Pin J-P, Kuhn R, Knöpfel T, Nicoletti F (1998) The metabotropic glutamate receptor mGlu5 controls the onset of developmental apoptosis in cultured cerebellar neurons. Eur J Neurosci 10:2173–2184

    PubMed  CAS  Google Scholar 

  56. Catania MV, Bellomo M, Di Giorgi-Gerevini V, Seminara G, Giuffrida R, Romeo R, De Blasi A, Nicoletti F (2001) Endogenous activation of group-I metabotropic glutamate receptors is required for differentiation and survival of cerebellar Purkinje cells. J Neurosci 21(19):7664–7673

    PubMed  CAS  Google Scholar 

  57. Ito M (2001) Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev 3:1143–1195

    Google Scholar 

  58. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136

    PubMed  CAS  Google Scholar 

  59. Maren S (2005) Synaptic mechanisms of associative memory in the amygdala. Neuron 47(6):783–786

    PubMed  CAS  Google Scholar 

  60. Pisani A, Centonze D, Bernardi G, Calabresi P (2005) Striatal synaptic plasticity: implications for motor learning and Parkinson’s disease. Mov Disord 20(4):395–402

    PubMed  Google Scholar 

  61. Bortolotto ZA, Fitzjohn SM, Collingridge GL (1999) Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus. Curr Opin Neurobiol 3:299–304

    Google Scholar 

  62. Bortolotto ZA, Collett VJ, Conquet F, Jia Z, van der Putten H, Collingridge GL (2005) The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors. Neuropharmacology 49(1):3–25

    Google Scholar 

  63. Riedel G, Reymann KG (1996) Metabotropic glutamate receptors in hippocampal long-term potentiation and learning and memory. Acta Physiol Scand 157(1):1–19

    PubMed  CAS  Google Scholar 

  64. Anwyl R (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev 29(1):83–120

    PubMed  CAS  Google Scholar 

  65. Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 17(13):5196–5205

    PubMed  CAS  Google Scholar 

  66. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    PubMed  CAS  Google Scholar 

  67. Linden DJ, Dickinson MH, Smeyne M, Connor JA (1991) A long term depression of AMPA currents in cultured cerebellar Purkinje neurons. Neuron 7:81–89

    PubMed  CAS  Google Scholar 

  68. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA, Tonegawa S (1994) Deficient cerebellar long term depression and impaired motor learning in mGluR1 mutant mice. Cell 79:377–388

    PubMed  CAS  Google Scholar 

  69. Shigemoto R, Abe T, Nomura S, Nakanishi S, Hirano T (1994) Antibodies inactivating mGluR1 metabotropic glutamate receptor block long-term depression in cultured Purkinje cells. Neuron 12:1245–1255

    PubMed  CAS  Google Scholar 

  70. Kano M, Hashimoto K, Kurihara H, Watanabe M, Inoue Y, Aiba A, Tonegawa S (1997) Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18(1):71–79

    PubMed  CAS  Google Scholar 

  71. Huber KM, Kayser MS, Bear MF (2000) Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent LTD. Science 288:1254–1257

    PubMed  CAS  Google Scholar 

  72. Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24(28):6352–6361

    PubMed  CAS  Google Scholar 

  73. Snyder EM, Philpot BD, Huber KM, Dong X, Fallon JR, Bear MF (2001) Internalization of ionotropic glutamate receptors in response to mGluR activation. Nat Neurosci 4(11):1079–1085

    PubMed  CAS  Google Scholar 

  74. Karachot L, Shirai Y, Vigot R, Yamamori T, Ito M (2001) Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein. Neurophysiology 86(1):280–289

    PubMed  CAS  Google Scholar 

  75. Dudek SM, Bear MF (1989) A biochemical correlate of the critical period for synaptic modification in the visual cortex. Science 246(4930):673–675

    PubMed  CAS  Google Scholar 

  76. Reid SNM, Romano C, Hughes T, Daw NW (1997) Developmental and sensory-dependent changes of phosphoinositide-linked metabotropic glutamate receptors. J Comp Neurol 389:577–583

    PubMed  CAS  Google Scholar 

  77. Hensch TK, Stryker MP (1996) Ocular dominance plasticity under metabotropic glutamate receptor blockade. Science 272(5261):554–557

    PubMed  CAS  Google Scholar 

  78. Huber KM, Sawtell NB, Bear MF (1998) Effects of the metabotropic glutamate receptor antagonist MCPG on phosphoinositide turnover and synaptic plasticity in visual cortex. J Neurosci 18(1):1–9

    PubMed  CAS  Google Scholar 

  79. Sawtell NB, Huber KM, Roder JC, Bear MF (1999) Induction of NMDA receptor-dependent long term depression in visual cortex does not require metabotropic glutamate receptors. J Neurophysiol 82(6):3594–3597

    PubMed  CAS  Google Scholar 

  80. Hannan AJ, Blakemore C, Katsnelson A, Vitalis T, Huber KM, Bear M, Roder J, Kim D, Shin H-S, Kind PC (2001) PLCβ1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nat Neurosci 4(3):282–288

    PubMed  CAS  Google Scholar 

  81. Spires TL, Molnar Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ (2005) Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb Cortex 15(4):385–393

    PubMed  Google Scholar 

  82. Vanderklish PW, Edelman GM (2002) Dendritic spines elongate after stimulation of group I metabotropic glutamate receptors in cultured hippocampal neurons. Proc Natl Acad Sci USA 99:1639–1644

    PubMed  CAS  Google Scholar 

  83. Grossman AW, Aldridge GM, Weiler IJ, Greenough WT (2006) Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. J Neurosci 26(27):7151–7155

    PubMed  CAS  Google Scholar 

  84. Jin P, Warren SR (2003) New insights into Fragile X syndrome: from molecules to neurobehaviors. Trends Biochem Sci 28(3):152–157

    PubMed  CAS  Google Scholar 

  85. Hagerman RJ, Hagerman P eds (2002) Fragile X syndrome: diagnosis, treatment and research, 3rd edn. The Johns Hopkins University Press, Baltimore, pp 3–109

    Google Scholar 

  86. Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 94:5401–5404

    PubMed  CAS  Google Scholar 

  87. Nimchinsky EA, Oberlander AM, Svoboda K (2001) Abnormal development of dendritic spines in FMR1 knock-out mice. J Neurosci 21(14):5139–5146

    PubMed  CAS  Google Scholar 

  88. Hinton VJ, Brown WT, Wisniewski K, Rudelli RD (1991) Analysis of neocortex in three males with the Fragile X syndrome. Am J Med Genet 41:289–294

    PubMed  CAS  Google Scholar 

  89. Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Koslowski PB, Swain RA, Weiler IJ, Greenough WT (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile X syndrome: a quantitative examination. Am J Med Genet 98:161–167

    PubMed  CAS  Google Scholar 

  90. Weiler IJ, Irwin SA, Klintsova AY, Spencer CM, Brazelton AD, Miyashiro K, Comery TA, Patel B, Eberwine J, Greenough WT (1997) Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci USA 94:5395–5400

    PubMed  CAS  Google Scholar 

  91. Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM (1997) Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci 17(5):1539–1547

    PubMed  CAS  Google Scholar 

  92. Antar LN, Afroz R, Dictenberg JB, Carrol RC, Bassel GJ (2004) Metabotropic glutamate receptor activation regulates Fragile X mental retardation protein and Fmr1 mRNA localization differentially in dendrites and at synapses. J Neurosci 24(11):2648–2655

    PubMed  CAS  Google Scholar 

  93. Khandjian EW, Huot ME, Tremblay S, Davidovic L, Mazroui R, Bardoni B (2004) Biochemical evidence for the association of Fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc Natl Acad Sci USA 101(36):13357–13362

    PubMed  CAS  Google Scholar 

  94. Stefani G, Fraser CE, Darnell JC, Darnell RB (2004) Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci 24(33):7272–7276

    PubMed  CAS  Google Scholar 

  95. Aschrafi A, Cunningham BA, Edelman GM, Vanderklish PW (2005) The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc Natl Acad Sci USA 102(6):2180–2185

    PubMed  CAS  Google Scholar 

  96. Miyashiro KY, Beckel-Mitchener A, Purk TP, Becker KG, Barret T, Liu L, Carbonetto S, Weiler IJ, Greenough WT, Eberwine J (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37(3):417–431

    PubMed  CAS  Google Scholar 

  97. Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (2003) The Fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNA at synapses. Cell 112:317–327

    PubMed  CAS  Google Scholar 

  98. Laggerbauer B, Ostarek D, Keidel EM, Ostarek-Lederer A, Fisher U (2001) Evidence that Fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet 10:329–338

    PubMed  CAS  Google Scholar 

  99. Li Z, Zhang Y, Ku L, Wilkinson KD, Warren ST, Feng Y (2001) Evidence that fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res 29:2276–2283

    PubMed  CAS  Google Scholar 

  100. Mazroui R, Huot ME, Tremblay S, Filion C, Labelle Y, Khandjian EW (2002) Trapping of messenger RNA by Fragile X mental retardation protein into cytoplasmic granules induces translation repression. Hum Mol Genet 11(24):3007–3017

    PubMed  CAS  Google Scholar 

  101. Qin M, Kang J, Burlin TBM, Jiang C, Smith CB (2005) Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neurosci 25(20):5087–5095

    PubMed  CAS  Google Scholar 

  102. Lu R, Wang H, Liang Z, Ku L, O’donnell WT, Li W, Warren ST, Feng Y (2004) The Fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci USA 101(42):15201–15206

    PubMed  CAS  Google Scholar 

  103. Todd PK, Mack KJ, Malter JS (2003) The Fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc Natl Acad Sci USA 100(24):14374–14378

    PubMed  CAS  Google Scholar 

  104. Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries E, Lambers FA, Hatia F, Base CK, Greenough WT (2004) Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci USA 101(50):17504–17509

    PubMed  CAS  Google Scholar 

  105. Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12(24):3295–3305

    PubMed  CAS  Google Scholar 

  106. Castets M, Schaeffer C, Bechara E, Schenk A, Khandjian EW, Luche S, Moine H, Rabilloud T, Mandel J-L, Bardoni B (2005) FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts. Hum Mol Genet 14(6):835–844

    PubMed  CAS  Google Scholar 

  107. Mao L, Yang L, Arora A, Choe ES, Zhang G, Liu Z, Fibuch EE, Wang JQ (2005) Role of protein phosphatase 2A in mGluR5-regulated MEK/ERK phosphorylation in neurons. J Biol Chem 280(13):12602–12610

    PubMed  CAS  Google Scholar 

  108. Garber K, Smith KT, Reines D, Warren ST (2006) Transcription, translation and Fragile X syndrome. Curr Opin Genet Dev 16(3):270–275

    PubMed  CAS  Google Scholar 

  109. Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of Fragile X mental retardation. Proc Natl Acad Sci USA 99:7746–7750

    PubMed  CAS  Google Scholar 

  110. Chuang S-C, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RKS (2005) Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a Fragile X mouse model. J Neurosci 25(35):8048–8055

    PubMed  CAS  Google Scholar 

  111. Bear MF, Huber KM, Warren ST (2004) The mGluR theory of Fragile X mental retardation. Trends Neurosci 27(7):370–377

    PubMed  CAS  Google Scholar 

  112. Wilson BM, Cox CL (2007) Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of Fragile X mice. Proc Natl Acad Sci USA 104:2454–2459

    PubMed  CAS  Google Scholar 

  113. Nosyreva ED, Huber KM (2006) Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of Fragile X syndrome. J Neurophysiol 95(5):3291–3295

    PubMed  CAS  Google Scholar 

  114. Hou L, Antion MD, Spencer CM, Paylor R, Klann E (2005) Altered mGluR-LTD in the Fmr1 knock-out and FMR1 YAC mouse models of fragile X mental retardation. Abstract no. 382.10, Abstract viewer/Itinerary planner. Society for Neuroscience, Washington, DC

    Google Scholar 

  115. Giuffrida R, Musumeci S, D’Antoni S, Bonaccorso MC, Giuffrida-Stella AM, Oostra BA, Catania MV (2005) A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive Homer proteins in a mouse model of Fragile X syndrome. J Neurosci 25(39):8908–8916

    PubMed  CAS  Google Scholar 

  116. Bear MF (2005) Therapeutic implications of the mGluR theory of Fragile X mental retardation. Genes Brain Behav 4(6):393–398

    PubMed  CAS  Google Scholar 

  117. McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK, Dockendorff TC, Nguyen HT, McDonald TC, Jongens TA (2005) Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of Fragile X syndrome. Neuron 45:753–764

    PubMed  CAS  Google Scholar 

  118. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major Fragile X syndrome mouse model phenotypes by the mGlu5 antagonist MPEP. Neuropharmacology 49:1053–1066

    PubMed  CAS  Google Scholar 

  119. Crino PB, Miyata H, Vinters HV (2002) Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 12(2):212–233

    PubMed  CAS  Article  Google Scholar 

  120. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB (2005) A developmental and genetic classification for malformations of cortical development. Neurology 65(12):1873–1887

    PubMed  CAS  Google Scholar 

  121. Sisodiya SM (2004) Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 3(1):29–38

    PubMed  Google Scholar 

  122. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y (1991) Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 30(6):750–757

    PubMed  CAS  Google Scholar 

  123. Palmini A, Gambardella A, Andermann F, Dubeau F, da Costa JC, Olivier A, Tampieri D, Gloor P, Quesnay F, Andermann E et al (1995) Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 37(4):476–487

    PubMed  CAS  Google Scholar 

  124. Aronica E, Leenstra S, van Veelen CW, van Rijen PC, Hulsebos TJ, Tersmette AC, Yankaya B, Troost D (2001) Glioneuronal tumors and medically intractable epilepsy: a clinical study with long-term follow-up of seizure outcome after surgery. Epilepsy Res 43(3):179–191

    PubMed  CAS  Google Scholar 

  125. Thom M (2004) Recent advances in the neuropathology of focal lesions in epilepsy. Expert Rev Neurother 4(6):973–984

    PubMed  Google Scholar 

  126. Tinkle BT, Schorry EK, Franz DN, Crone KR, Saal HM (2005) Epidemiology of hemimegalencephaly: a case series and review. Am J Med Genet A 139(3):204–211

    PubMed  Google Scholar 

  127. Flores-Sarnat L (2002) Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 17(5):373–384

    PubMed  Google Scholar 

  128. Sarnat HB, Flores-Sarnat L (2004) Integrative classification of morphology and molecular genetics in central nervous system malformations. Am J Med Genet A 126(4):386–392

    PubMed  Google Scholar 

  129. Jonas R, Nguyen S, Hu B, Asarnow RF, LoPresti C, Curtiss S, de Bode S, Yudovin S, Shield WD, Vinters HV, Mathern GW (2004) Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 62(10):1712–1721

    PubMed  CAS  Google Scholar 

  130. Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, Foldvary-Schaefer N, Jackson G, Luders HO, Prayson R, Spreafico R, Vinters HV (2004) Terminology and classification of the cortical dysplasias. Neurology 62(6 Suppl 3):S2–S8

    PubMed  CAS  Google Scholar 

  131. Ferrier CH, Aronica E, Leijten FSS, Spliet WGM, van Huffelen AC, van Rijen PC, Binnie CD (2006) Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia. Epilepsia 47(9):1477–1486

    PubMed  Google Scholar 

  132. Najm I, Ying Z, Babb T, Crino PB, Macdonald R, Mathern GW, Spreafico R (2004) Mechanisms of epileptogenicity in cortical dysplasias. Neurology 62(6 Suppl 3):S9–S13

    PubMed  CAS  Google Scholar 

  133. Wong RK, Chuang SC, Bianchi R (2004) Plasticity mechanisms underlying mGluR–induced epileptogenesis. Adv Exp Med Biol 548:69–75

    PubMed  CAS  Google Scholar 

  134. Moldrich RX, Chapman AG, De Sarro G, Meldrum BS (2003) Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Eur J Pharmacol 476(1–2):3–16

    PubMed  CAS  Google Scholar 

  135. Aronica E, Yankaya B, Jansen GH, Leenstra S, van Veelen CW, Gorter JA, Troost D (2001) Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol 27(3):223–237

    PubMed  CAS  Google Scholar 

  136. Aronica E, Gorter JA, Jansen GH, van Veelen CW, van Rijen PC, Ramkema M, Troost D (2003) Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia. Epilepsia 44(6):785–795

    PubMed  CAS  Google Scholar 

  137. Akbar MT, Rattray M, Powell JF, Meldrum BS (1996) Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats. Brain Res Mol Brain Res 43(1–2):105–116

    PubMed  CAS  Google Scholar 

  138. Aronica EM, Gorter JA, Paupard MC, Grooms SY, Bennett MV, Zukin RS (1997) Status epilepticus-induced alterations in metabotropic glutamate receptor expression in young and adult rats. J Neurosci 17(21):8588–8595

    PubMed  CAS  Google Scholar 

  139. Blumcke I, Becker AJ, Klein C, Scheiwe C, Lie AA, Beck H, Waha A, Friedl MG, Kuhn R, Emson P, Elger C, Westler OD (2000) Temporal lobe epilepsy associated up-regulation of metabotropic glutamate receptors: correlated changes in mGluR1 mRNA and protein expression in experimental animals and human patients. J Neuropathol Exp Neurol 59(1):1–10

    PubMed  CAS  Google Scholar 

  140. Winder DG, Ritch PS, Gereau RWT, Conn PJ (1996) Novel glial-neuronal signalling by coactivation of metabotropic glutamate and beta-adrenergic receptors in rat hippocampus. J Physiol (Lond) 494(Pt 3):743–755

    CAS  Google Scholar 

  141. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron -to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosi 6(1):43–50

    CAS  Google Scholar 

  142. Ciccarelli R, Sureda FX, Casabona G, Di Iorio P, Caruso A, Spinella F, Condorelli DF, Nicoletti F, Caciagli F (1997) Opposite influence of the metabotropic glutamate receptor subtypes mGlu3 and -5 on astrocyte proliferation in culture. Glia 21(4):390–398

    PubMed  CAS  Google Scholar 

  143. Bruno V, SUreda FX, Storto M, Casabona G, Caruso A, Knopfel T, Kuhn R, Nicoletti F (1997) The neuroprotective activity of group-II metabotropic glutamate receptors require new protein synthesis and involves a glial-neuronal signaling. J Neurosci 17(6):1891–1897

    PubMed  CAS  Google Scholar 

  144. Bruno V, Battaglia G, Casabona G, Copani A, Caciagli F, Nicoletti F (1998) Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J Neurosci 18(23):9594–9600

    PubMed  CAS  Google Scholar 

  145. Ciccarelli R, Di Iorio P, Bruno V, Battaglia G, D’Alimonte I, D’Onofrio M, Nicoletti F, Caciagli F (1999) Activation of A(1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocytes. Glia 27(3):275–281

    PubMed  CAS  Google Scholar 

  146. Aronica E, Gorter JA, Rozemuller AJ, Yankaya B, Troost D (2005) Activation of metabotropic glutamate receptor 3 enhances interleukin (IL)-1beta-stimulated release of IL-6 in cultured human astrocytes. Neuroscience 130(4):927–933

    PubMed  CAS  Google Scholar 

  147. Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37(2–3):163–170

    PubMed  CAS  Google Scholar 

  148. Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Troost D (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 17(10):2106–2118

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Vincenza Catania.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Catania, M.V., D’Antoni, S., Bonaccorso, C.M. et al. Group I Metabotropic Glutamate Receptors: A Role in Neurodevelopmental Disorders?. Mol Neurobiol 35, 298–307 (2007). https://doi.org/10.1007/s12035-007-0022-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-007-0022-1

Keywords

  • Neural development
  • Plasticity
  • Metabotropic glutamate receptors
  • mGluRs
  • Fragile X syndrome
  • FRAX
  • Epilepsy
  • Malformation of cortical development