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Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats

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Abstract

Rationale

Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved in neuronal plasticity, and disturbance in vigilance states and cortical network connectivity contribute significantly to cognitive deficits described in schizophrenia and Alzheimer’s disease. Here, we examined the circadian changes of mGluR5 density and the functional response to modulation of mGluR5 signaling.

Methods

The current study carried out in Sprague-Dawley rats quantified the density of mGluR5 across the light-dark cycle with autoradiography. The central activity of mGluR5 negative allosteric modulators (2-methyl-6-(phenylethynyl)pyridine (MPEP) and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and positive allosteric modulators (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone (ADX47273) and (7S)-3-tert-butyl-7-[3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (LSN2814617) was examined on sleep-wake architecture. The functional effect of mGluR5 modulation on cortical networks communication was described in freely moving animals.

Results

The density of mGluR5 in the striatal, cortical, hippocampal and thalamic structures was unchanged across the light-dark cycle. Allosteric blockade of mGluR5 consistently consolidated deep sleep, enhanced sleep efficiency and elicited prominent functional coherent network activity in slow theta and gamma oscillations. However, allosteric activation of mGluR5 increased waking, decreased deep sleep and reduced functional network connectivity following the activation of slow alpha oscillatory activity.

Conclusion

This functional study differentiates the pharmacology of allosteric blockade of mGluR5 from that of allosteric activation and suggests that mGluR5 blockade enhances sleep and facilitates oscillatory network connectivity, both processes being known to have relevance in cognition processes.

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References

  • Ahnaou A, Dautzenberg FM, Geys H, Imogai H, Gibelin A, Moechars D, Steckler T, Drinkenburg WHIM (2009) Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep-wake architecture. Eur J Pharmacol 603:62–72

    Article  CAS  PubMed  Google Scholar 

  • Ahnaou A, Huysmans H, Jacobs T, Drinkenburg WHIM (2014) Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential. Neuropharmacology 86C:362–377

    Article  Google Scholar 

  • 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. 20:323–9

  • Balázs R, Miller S, Romano C, de Vries A, Chun Y, Cotman CW (1997) Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation. J Neurochem 6:151–163

    Google Scholar 

  • Basar E (2012) A review of alpha activity in integrative brain function. Fundamental physiology, sensory coding, cognition and pathology. Int J Pschophysiol 1–24

  • Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep-wake regulation. Prog Neurobiol 73:379–396

    Article  CAS  PubMed  Google Scholar 

  • Benchenane K, Tiesinga PH, Battaglia FP (2011) Oscillations in the prefrontal cortex: a gateway to memory and attention. Curr Opin Neurobiol 21:475–485

    Article  CAS  PubMed  Google Scholar 

  • Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266–271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Breysse N, Amalric M, Salin P (2003) Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats. J Neurosci 23:8302–8309

    CAS  PubMed  Google Scholar 

  • Bruton RK, Ge J, Barnes NM (1999) Group I mGlu receptor modulation of dopamine release in the rat striatum in vivo. Eur J Pharmacol 369:175–181

    Article  CAS  PubMed  Google Scholar 

  • Busse J, Brodkin D, Tattersall JJ, Anderson N, Warren L, Tehrani LJ, Bristow MA, Varney ND, Cosford ND (2004) The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology 29:1971–1979

    Article  CAS  PubMed  Google Scholar 

  • Buzsáki G (2002) Theta oscillations in the hippocampus. Neuron 33:325–340

    Article  PubMed  Google Scholar 

  • Cantero JL, Atienza M (2005) The role of neural synchronization in the emergence of cognition across the wake-sleep cycle. Rev Neurosci 16: 69–83

  • Cappaert NL, Lopes da Silva FH, Wadman WJ (2009) Spatio-temporal dynamics of theta oscillations in hippocampal-enthorinal slices. Hippocampus 19:1065–77

  • Cavas M, Scesa G, Navarro JF (2013) Effects of MPEP, a selective metabotropic glutamate mGlu5 ligand, on sleep and wakefulness in the rat. Prog Neuropsychopharmacol Biol Psychiatry 40:18–25

    Article  CAS  PubMed  Google Scholar 

  • Chatfield C (1975) The analysis of time series: an introduction. Chapman and Hall, London

    Google Scholar 

  • Cosford ND, Roppe J, Tehrani L, Schweiger EJ, Seiders TJ, Chaudary A, Rao S, Varney MA (2003) [3H]-Methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg Med Chem Lett 13:351–354

    Article  CAS  PubMed  Google Scholar 

  • Dang-Vu TT, Schabus M, Desseilles M, Albouy G, Boly M, Darsaud A, Gais S, Rauchs G, Sterpenich V, Vandewalle G, Carrier J, Moonen G, Balteau E, Degueldre C, Luxen A, Phillips C, Maquet P (2008) Spontaneous neural activity during human slow wave sleep. Proc Natl Acad Sci U S A 105:15160--5

  • Debener S, Hermann CS, Kranczioch C, Gembris D, Engel AK (2003) Top-down attentional processing enhances auditory evoked gamma band activity. Neuroreport 14:683–686

    Article  PubMed  Google Scholar 

  • De Leonibus E, Managò F, Giordani F, Petrosino F, Lopez S, Oliverio A, Amalric M, Mele A (2009) Metabotropic glutamate receptors 5 blockade reverses spatial memory deficits in a mouse model of Parkinson's disease. Neuropsychopharmacology 34:729--38

  • Diekelmann S, Wilhelm I, Born J (2009) The whats and whens of sleep-dependent memory consolidation. Sleep Med Rev 13:309–321

    Article  PubMed  Google Scholar 

  • Fell J, Klavers P, Lehnertz K, Grunwald T, Schaller C, Elger CE, Fernandez G (2001) Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling. Nat Neurosci 4:1259–1264

    Article  CAS  PubMed  Google Scholar 

  • Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483–504

    Article  CAS  PubMed  Google Scholar 

  • Ford JM, Gray M, Faustman WO, Heinks TH, Mathalon DH (2005) Reduced gamma-band coherence to distorted feedback during speech when what you say is not what you hear. Int J Psychophysiol 57:143–150

    Article  PubMed  Google Scholar 

  • Foxe JJ, Simpson GV, Ahlfors SP (1998) Parieto-occipital approximately 10 Hz activity reflects anticipatory state of visual attention mechanisms. Neuropreport 9:3929--33

  • 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. Neuropharmacol 38:1493–1503

    Article  CAS  Google Scholar 

  • Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W (2008) mGluR5 antagonists: discovery, characterization and drug development. Curr Opin Drug Discov Dev 11:655–665

    CAS  Google Scholar 

  • Gilmour G, Broad LM, Wafford KA, Britton T, Colvin EM, Fivush A, Gastambide F, Getman B, Heinz BA, McCarthy AP, Prieto L, Shanks E, Smith JW, Taboada L, Edgar DM, Tricklebank MD (2013) In vitro characterization of the novel positive allosteric modulators of the mGlu5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. Neuropharmacol 64:224–239

    Article  CAS  Google Scholar 

  • Gray L, van den Buuse M, Scarr E, Dean B, Hannan AJ (2009) Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation. Int J Neuropsychopharmacol 12:45–60

    Article  CAS  PubMed  Google Scholar 

  • Guadagna S, Bundgaard C, Hovelsø N, Volbracht C, Francis PT, Egebjerg J, Sotty F (2012) Memantine potentiates hippocampal θ oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties. Neuropharmacology 62:2208–2218

    Article  CAS  PubMed  Google Scholar 

  • Hasan S, Ahnaou A, Drinkenburg WHIM, Tafti M, Franken P (2009) How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychopharmacology 34:1625–1640

    Article  CAS  PubMed  Google Scholar 

  • Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM, Scheidegger M, Berthold T, Gomez-Mancilla B, Seifritz E, Landolt HP (2013) Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry 73:161–168

    Article  CAS  PubMed  Google Scholar 

  • Heidbreder CA, Bianchi M, Lacroix LP, Faedo S, Perdona E, Remelli CP, Crespi F (2003) Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo. Synapse 50:269–276

    Article  CAS  PubMed  Google Scholar 

  • Herrmann CS, Demiralp T (2005) Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol 116:2719–2733

    Article  CAS  PubMed  Google Scholar 

  • Herrmann CS, Frund I, Lenz D (2010) Human gamma-band activity: a review on cognitive and behavioral correlates and network models. Neurosci Biobehav Rev 34:981–992

    Article  PubMed  Google Scholar 

  • Ishida T, Obara Y, Kamei C (2010) Studies on wakefulness-promoting effect of memantine in rats. Behav Brain Res 206:274–278

    Article  CAS  PubMed  Google Scholar 

  • Jensen O, Mazaheri A (2010) Shaping functional architecture by oscillatory alpha activity: gating by inhibition. Front Hum Neurosci 4:186

    Article  PubMed Central  PubMed  Google Scholar 

  • Jew CP, Wu CS, Sun H, Zhu J, Huang JY, Yu D, Justice NJ, Lu HC (2013) mGluR5 ablation in cortical glutamatergic neurons increases novelty-induced locomotion. PLoS ONE 8:e70415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jokisch D, Jensen O (2007) Modulation of gamma and alpha activity during a working memory task engaging the dorsal or ventral stream. J Neurosci 27: 3244--51

  • Kaiser J, Lutzenberger W (2009) Induced gamma-band activity and human brain function. Neuroscientist 9:475--84

  • Klimesch W, Sauseng P, Hanslmavr S (2007) EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev 53:63–88

    Article  PubMed  Google Scholar 

  • Kniazeff J, Bessis AS, Maurel D, Ansanay H, Prézeau L, Pin JP (2004) Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol 11:706--13

  • Kocsis B, Bragin A, Buzsáki G (1999) Interdependence of multiple theta generators in the hippocampus: a partial coherence analysis. J Neurosci 19:6200–6212

    CAS  PubMed  Google Scholar 

  • Kodama T, Lai YY, Siegel JM (1998) Enhanced glutamate release during REM sleep in the rostromedial medulla as measured by in vivo microdialysis. Brain Res 780:178–181

    Article  CAS  PubMed  Google Scholar 

  • Laufs H, Holt JL, Elfont R, Krams M, Paul JS, Krakow K, Kleinshmidt A (2006) Where the BOLD signal goes when alpha EEG leaves. Neuroimage 31:1408–1418

    Article  CAS  PubMed  Google Scholar 

  • Lea PM, Faden AI (2006) Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev Summer 12:149–166

    Article  CAS  Google Scholar 

  • Lisman J, Buzsàki G (2008) A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophr Bull 4:974--80

  • Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulcicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL (2008) ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther 327:827–839

    Article  CAS  PubMed  Google Scholar 

  • Lopes da Silva FH, Vos JE, Mooibroek J, Vaan Rotterdam A (1980) Relative contributions of intracortical and thalamo-cortical process in the generation of alpha rhythms, revealed partial coherence analysis. Electroencephalogr Clin Neurophysiol 50:449–456

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Rodriguez F, Medina-Ceja L, Wilson CL, Jhung CL, Morales-Villagram A (2007) Changes in extracellular glutamate levels in rat orbitofrontal cortex during sleep and wakefulness. Arch Med Res 38:52–55

    Article  CAS  PubMed  Google Scholar 

  • Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM (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

    CAS  PubMed  Google Scholar 

  • Lujan R, Shgemoto 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

    Article  CAS  PubMed  Google Scholar 

  • Mander BA, Rao V, Lu B, Saletin JM, Lindquist JR, Ancoli-Israel S, Jagust W, Walker MP (2013) Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci 16:357–364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maquet P, Degueldre C, Delfiore G, Aerts J, Péters JM, Luxen A, Franck G. (1997) Functional neuroanatomy of human slow wave sleep. J Neurosci. 17:2807--12

  • Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C, Hagenbuchle O, O’Hara BF, Franken P, Tafti M (2007) Homer1a is a core brain molecular correlate of sleep loss. Proc Natl Acad Sci U S A 104:20090–20095

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mathiesen JM, Svendsen N, Bräuner-Osborne H, Thomsen C, Ramirez MT (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br J Pharmacol 138:1026–1030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McCoy JG, Strecker RE (2011) The cognitive cost of sleep lost. Neurobiol Learn Mem 96:564–582

    Article  PubMed Central  PubMed  Google Scholar 

  • Michalon A, Bruns A, Risterucci C, Honer M, Ballard TM, Ozmen L, Jaeschke G, Wettstein JG, von Kienlin M, Künnecke B, Lindemann L (2013) Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice. Biol Psychiatry 75:189–197

    Article  PubMed  Google Scholar 

  • Montgomery SM, Sirota A, Buzsáki G (2008) Theta and gamma coordination of hippocampal networks during waking and rapid eye movement sleep. J Neurosci 28:6731–6741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Movsesyan VA, O'Leary DM, Fan L, Bao W, Mullins PG, Knoblach SM, Faden AI (2001) mGluR5 antagonists 2-methyl-6- (phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 296:41--7

  • Naidoo N, Ferber M, Galante RJ, McShane B, Hu JH, Zimmerman J, Maislin G, Cater J, Wyner A, Worley P, Pack AI (2012) Role of Homer proteins in the maintenance of sleep-wake states. PLoS ONE 7:e35174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Naylor E, Aillon DV, Gabbert S, Harmon H, Johnson DA, Wilson GS, Petillo PA (2011) Simultaneous real-time measurement of EEG/EMG and L-glutamate in mice: a biosensor study of neuronal activity during sleep. J Electroanal Chem 656:106–113

    Article  CAS  Google Scholar 

  • O’Leary DM, Movsesyan V, Vicini S, Faden AI (2000) Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br J Pharmacol 131:1429–1437

    Article  PubMed Central  PubMed  Google Scholar 

  • Parmentier-Batteur S, O’Brien JA, Doran S, Nguyen SJ, Flick RB, Uslaner JM, Chen H, Finger EN, Williams TM, Jacobson MA, Hutson PH (2012) Differential effects of the mGluR5 positive allosteric modulator CDPPB in the cortex and striatum following repeated administration. Neuropharmacology 62:1453–1460

    Article  CAS  PubMed  Google Scholar 

  • Paul IA, Skolnick P (2003) Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci 1003: 250--72

  • Paz R, Bauer EP, Paré D (2008) Theta synchronizes the activity of medial prefrontal neurons during learning. Learn Mem 15:524–531

    Article  PubMed Central  PubMed  Google Scholar 

  • Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan T (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 2:129–133

    Article  CAS  PubMed  Google Scholar 

  • Phillips WA, Silverstein SM (2003) Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav Brain Sci 26:65–82

    PubMed  Google Scholar 

  • Pietraszek M, Gravius A, Schäfer D, Weil T, Trifanova D, Danysz W (2005) mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 49:73–85

    Article  CAS  PubMed  Google Scholar 

  • Priestley MB (1981) Spectral analysis and time series, vol 1–2. Elsevier Academic, London

    Google Scholar 

  • Renoldi G, Cacagno E, Borsini F, Invernizzi RW (2007) Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex. J Neurochem 100:1658–1666

    CAS  PubMed  Google Scholar 

  • Sederberg PB, Kahana MJ, Howard MW, Donner EJ, Madsen JR (2003) Theta and gamma oscillations during encoding predict subsequent recall. J Neurosci 23:10809–10814

    CAS  PubMed  Google Scholar 

  • Seemuler A, Muller EM, Rosler (2012) EEG-power and -coherence changes in a unimodal and a crossmodal working memory task with visual and kinesthetic stimuli. Int J Psychophysiol 83:87--95

  • Shigemoto R, Nomura S, Ohishi H, Sugihara H, Nakanishi S, Mizuno N (1993) Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett 163:53–57

    Article  CAS  PubMed  Google Scholar 

  • Schmidt B, Hinman JR, Jacobson TK, Szkudlarek E, Argraves M, Escabí MA, Markus EJ (2013) Dissociation between dorsal and ventral hippocampal theta oscillations during decision-making. J Neurosci 33:6212--24

  • Simonyi A, Schachtman TR, Chritoffersen GR (2010) Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur J Pharmacol 639(1-3):17--25

  • Singer W (2011) Dynamic formation of functional networks by synchronization. Neuron 69:191--3

  • Smolders I, Clinckers R, Meurs A, De Bundel D, Portelli J, Ebinger G, Michotte Y (2008) Direct enhancement of hippocampal dopamine or serotonin levels as a pharmacodynamic measure of combined antidepressant-anticonvulsant action. Neuropharmacology 54:1017–1028

    Article  CAS  PubMed  Google Scholar 

  • Spooren W, Ballard T, Gasparini F, Amalric M, Mutel V, Schreiber R (2003) Insight into the function of group I and group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders. Behav Pharmacol 14:257–277

    Article  CAS  PubMed  Google Scholar 

  • Stachowicz K, Gołembiowska K, Sowa M, Nowak G, Chojnacka-Wójcik E, Pilc A (2007) Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent. Neuropharmacology 53:741–748

    Article  CAS  PubMed  Google Scholar 

  • Stickgold R, Walker MP (2013) Sleep-dependent memory triage: evolving generalization through selective processing. Nat Neurosci 16:139–145

    Article  CAS  PubMed  Google Scholar 

  • Summerfield C, Mangels JA (2005) Functional coupling between frontal and parietal lobes during recognition memory. Neuroreport 16:117–122

    Article  PubMed  Google Scholar 

  • Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4:131–144

    Article  CAS  PubMed  Google Scholar 

  • Tallon-Baudry C (2004) Attention and awareness in synchrony. Trends Cogn Sci 12:523–525

    Article  Google Scholar 

  • Thatcher RW (2012) Coherence, phase differences, phase shift, and phase lock in EEG/ERP analyses. Dev Neuropsychol 37:476–496

    Article  PubMed  Google Scholar 

  • Thierry AM, Gioanni Y, Dégénétais E, Glowinski J (2000) Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus 10:411–419

    Article  CAS  PubMed  Google Scholar 

  • Thomas LS, Jane DE, Harris JR, Croucher MJ (2000) Metabotropic glutamate autoreceptors of the mGlu(5) subtype positively modulate neuronal glutamate release in the rat forebrain in vitro. Neuropharmacology 39:1554--66

  • Thomas NK, Wright RA, Howson PA, Kingston AE, Schoepp DD, Jane DE (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 40:311–318

    Article  CAS  PubMed  Google Scholar 

  • Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodson RA, Lu SX, Niclussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R (2005) The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology 179:207–217

    Article  CAS  PubMed  Google Scholar 

  • Verbeke G, Molenberghs G (2000) Linear mixed models for longitudinal data. Springer Series in Statistics. Springer, New York

    Google Scholar 

  • Vertes RP (2005) Hippocampal theta rhythm: a tag for short-term memory. Hippocampus 15:923–935

    Article  CAS  PubMed  Google Scholar 

  • Vinueza Veloz MF, Buijsen RA, Willemsen R, Cupido A, Bosman LW, Koekkoek SK, Potters JW, Oostra BA, De Zeeuw CI (2012) The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice. Genes Brain Behav 11:325–331

    Article  CAS  PubMed  Google Scholar 

  • Whittington MA, Faulkner HJ, Doheny HC, Traub RD (2000) Neuronal fast oscillations as a target site for psychoactive drugs. Pharmacol Ther 86:171–190

    Article  CAS  PubMed  Google Scholar 

  • Womelsdorf T, Fries P (2006) neuronal cohercence during selective attentional processing and sensory-motor integration. J Physiol Paris 100:182--93

  • Wulff P, Ponomarenko AA, Bartos M, Korotkova TM, Fuchs EC, Bähner F, Both M, Tort AB, Kopell NJ, Wisden W, Monyer H (2009) Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons. Proc Natl Acad Sci U S A 106:3561–3566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the technical assistance of Mrs. Heidi Huysmans and Paula Te Riele.

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Authors and Affiliations

  1. Department of Neuroscience, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    A. Ahnaou, X. Langlois, T. Steckler & W. H. I. M. Drinkenburg

  2. Neuroscience Medicinal Chemistry, Janssen-Cilag S.A., Jarama 75, Polígono Industrial, 45007, Toledo, Spain

    J. M. Bartolome-Nebreda

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  1. A. Ahnaou
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Ahnaou, A., Langlois, X., Steckler, T. et al. Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats. Psychopharmacology 232, 1107–1122 (2015). https://doi.org/10.1007/s00213-014-3746-4

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