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mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

An Erratum to this article was published on 09 March 2016

Abstract

Rationale

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.

Objectives

We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.

Methods

Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions.

Results

In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine.

Conclusions

We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

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References

  • Adams DH, Kinon BJ, Baygani S, Millen BA, Velona I, Kollack-Walker S, Walling DP (2013) A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatr 13:143. doi:10.1186/1471-244X-13-143

    Article  Google Scholar 

  • Agim ZS, Esendal M, Briollais L, Uyan O, Meschian M, Martinez LAM, Ding Y, Basak AN, Ozcelik H (2013) Discovery, validation and characterization of Erbb4 and Nrg1 haplotypes using data from three genome-wide association studies of schizophrenia. PLoS ONE 8:e53042. doi:10.1371/journal.pone.0053042

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Amitai N, Markou A (2010) Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats. Eur J Pharmacol 639:67–80. doi:10.1016/j.ejphar.2009.12.040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Barzilay R, Ben-Zur T, Sadan O et al. (2011) Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice. Translat Psychiatr 1

  • Benes FM, Khan Y, Vincent SL, Wickramasinghe R (1996a) Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain. Synapse 22:338–349. doi:10.1002/(SICI)1098-2396(199604)22:4<338::AID-SYN5>3.0.CO;2-C

    CAS  Article  PubMed  Google Scholar 

  • Benes FM, Vincent SL, Marie A, Khan Y (1996b) Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75:1021–1031

    CAS  Article  PubMed  Google Scholar 

  • Beninger RJ, Beuk J, Banasikowski TJ, van Adel M, Boivin GA, Reynolds JN (2010) Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABAA receptor binding. Behav Pharmacol 21:1–10. doi:10.1097/FBP.0b013e3283347091

    CAS  Article  PubMed  Google Scholar 

  • Blot K, Kimura S-I, Bai J, Kemp A, Manahan-Vaughan D, Giros B, Tzavara E, Otani S (2013) Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801. Cereb Cortex. doi:10.1093/cercor/bht329

    PubMed  Google Scholar 

  • Brown AS (2010) The environment and susceptibility to schizophrenia. Prog Neurobiol. doi:10.1016/j.pneurobio.2010.09.003

    PubMed Central  Google Scholar 

  • Bullock WM, Bolognani F, Botta P, Valenzuela CF, Perrone-Bizzozero NI (2009) Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine. Neurochem Int 55:775–782

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Buonanno A (2010) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. Brain Res Bull 83:122–131. doi:10.1016/j.brainresbull.2010.07.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Bustillo J, Galloway MP., Ghoddoussi F et al. (2012) Medial-frontal cortex hypometabolism in chronic phencyclidine exposed rats assessed by high resolution magic angle spin 11.7T proton magnetic resonance spectroscopy. Neurochem Int. doi:10.1016/j.neuint.2012.04.003

  • Callaghan RC, Cunningham JK, Allebeck P, Arenovich T, Sajeev G, Remington G, Boileau I, Kish SJ (2012) Methamphetamine use and schizophrenia: a population-based cohort study in California. Am J Psychiatry 169:389–396. doi:10.1176/appi.ajp.2011.10070937

    Article  PubMed  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170

    CAS  PubMed  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (2000) Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine. Psychopharmacology 148:423–429

    CAS  Article  PubMed  Google Scholar 

  • Clark M, Johnson BG, Wright RA, Monn JA, Schoepp DD (2002) Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats. Pharmacol Biochem Behav 73:339–346

    CAS  Article  PubMed  Google Scholar 

  • Corbett R, Zhou L, Sorensen SM, Mondadori C (1999) Animal models of negative symptoms: M100907 antagonizes PCP-induced immobility in a forced swim test in mice. Neuropsychopharmacology 21:S211–S218

    CAS  Article  Google Scholar 

  • Corti C, Crepaldi L, Mion S, Roth AL, Xuereb JH, Ferraguti F (2007) Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia. Biol Psychiatry 62:747–755. doi:10.1016/j.biopsych.2006.12.005

    CAS  Article  PubMed  Google Scholar 

  • Dean B, Karl T, Pavey G, Boer S, Duffy L, Scarr E (2008) Increased levels of serotonin 2A receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice. Schizophr Res 99:341–349. doi:10.1016/j.schres.2007.10.013

    Article  PubMed  Google Scholar 

  • Desbonnet L, Waddington JL, Tuathaigh CM (2009) Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes? Behav Brain Res 204:258–273

    CAS  Article  PubMed  Google Scholar 

  • Drew GM, Vaughan CW (2004) Multiple metabotropic glutamate receptor subtypes modulate GABAergic neurotransmission in rat periaqueductal grey neurons in vitro. Neuropharmacology 46:927–934. doi:10.1016/j.neuropharm.2004.01.015

    CAS  Article  PubMed  Google Scholar 

  • du Bois TM, Deng C, Han M, et al (2009) Excitatory and inhibitory neurotransmission is chronically alteredfollowing perinatal NMDA receptor blockade. Eur Neuropsychopharmacol 19:256–65. doi:10.1016/j.euroneuro.2008.12.002

  • Duncan CE, Webster MJ, Rothmond DA, Bahn S, Elashoff M, Shannon Weickert C (2010) Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia. J Psychiatr Res 44:673–681. doi:10.1016/j.jpsychires.2009.12.007

    Article  PubMed  Google Scholar 

  • Elsworth JD, Morrow BA, Hajszan T, Leranth C, Roth RH (2011) Phencyclidine-induced loss of asymmetric spine synapses in rodent prefrontal cortex is reversed by acute and chronic treatment with olanzapine. Neuropsychopharmacology 36:2054–2061. doi:10.1038/npp.2011.96

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Errico F, Napolitano F, Squillace M, Vitucci D, Blasi G, de Bartolomeis A, Bertolino A, D’Aniello A, Usiello A (2013) Decreased levels of D-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia. J Psychiatr Res 47:1432–1437. doi:10.1016/j.jpsychires.2013.06.013

    Article  PubMed  Google Scholar 

  • Frank E, Newell KA, Huang XF (2011) Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age. Schizophr Res 128:56–60. doi:10.1016/j.schres.2011.01.008

    Article  PubMed  Google Scholar 

  • Geddes AE, Huang X-F, Newell KA (2011) Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:896–904. doi:10.1016/j.pnpbp.2011.02.017

    CAS  Article  PubMed  Google Scholar 

  • Geddes AE, Huang X-F, Newell KA (2014) GluN2B protein deficits in the left, but not the right, hippocampus in schizophrenia. BMC Psychiatr 14:274

    Article  Google Scholar 

  • Ghose S, Gleason KA, Potts BW, Lewis-Amezcua K, Tamminga CA (2009) Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action? Am J Psychiatr 166:812–820. doi:10.1176/appi.ajp.2009.08091445

    Article  PubMed  PubMed Central  Google Scholar 

  • Gleason SD, Shannon HE (1997) Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology (Berl) 129:79–84

    CAS  Article  Google Scholar 

  • González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97. doi:10.1038/nature06612

    Article  PubMed  PubMed Central  Google Scholar 

  • Gorrie GH, Vallis Y, Stephenson A, Whitfield J, Browning B, Smart TG, Moss SJ (1997) Assembly of GABAA receptors composed of alpha1 and beta2 subunits in both cultured neurons and fibroblasts. J Neurosci 17:6587–6596

    CAS  PubMed  Google Scholar 

  • Gu G, Lorrain DS, Wei H, Cole RL, Zhang X, Daggett LP, Schaffhauser HJ, Bristow LJ, Lechner SM (2008) Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: implication in emotional responses and central disinhibition. Brain Res 1197:47–62. doi:10.1016/j.brainres.2007.12.057

    CAS  Article  PubMed  Google Scholar 

  • Gupta DS, McCullumsmith RE, Beneyto M, Haroutunian V, Davis KL, Meador Woodruff JH (2005) Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse 57:123–131. doi:10.1002/syn.20164

    CAS  Article  PubMed  Google Scholar 

  • Hanania T, Hillman GR, Johnson KM (1999) Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit. Synapse 31:229–239. doi:10.1002/(SICI)1098-2396(19990301)31:3<229::AID-SYN8>3.0.CO;2-3

    CAS  Article  PubMed  Google Scholar 

  • Harich S, Gross G, Bespalov A (2007) Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology 192:511–519

    CAS  Article  PubMed  Google Scholar 

  • Hashimoto K, Malchow B, Falkai P, Schmitt A (2013) Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263:367–377. doi:10.1007/s00406-013-0399-y

    Article  PubMed  Google Scholar 

  • Hikichi H, Kaku A, Karasawa J, Chaki S (2013) Stimulation of metabotropic glutamate (mGlu) 2 receptor and blockade of mGlu1 receptor improve social memory impairment elicited by MK-801 in rats. J Pharmacol Sci 122:10–16

    CAS  Article  PubMed  Google Scholar 

  • Hiyoshi T, Kambe D, Karasawa J, Chaki S (2014) Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms. Neuroscience 280:262–274. doi:10.1016/j.neuroscience.2014.08.047

    CAS  Article  PubMed  Google Scholar 

  • Hu W, MacDonald ML, Elswick DE, Sweet RA (2014) The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci 1338:38–57. doi:10.1111/nyas.12547

    Article  PubMed  PubMed Central  Google Scholar 

  • Imre G (2007) The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268. CNS Drug Rev 13:444–464. doi:10.1111/j.1527-3458.2007.00024.x

    CAS  PubMed  Google Scholar 

  • Imre G, Salomons A, Jongsma M, Fokkema DS, Den Boer JA, Ter Horst GJ (2006) Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat. Pharmacol Biochem Behav 84:392–399. doi:10.1016/j.pbb.2006.05.021

    CAS  Article  PubMed  Google Scholar 

  • Inan M, Petros TJ, Anderson SA (2013) Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia. Neurobiol Dis 53:36–48. doi:10.1016/j.nbd.2012.11.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Javitt DC (2010) Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci 47:4–16

    PubMed  Google Scholar 

  • Kapur S, VanderSpek SC, Brownlee BA, Nobrega JN (2003) Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 305:625–631. doi:10.1124/jpet.102.046987

    CAS  Article  PubMed  Google Scholar 

  • Karl T, Arnold JC (2014) Schizophrenia: a consequence of gene-environment interactions? Front Behav Neurosci 8

  • Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR (2007) Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav 6:677–687

    CAS  Article  PubMed  Google Scholar 

  • Katayama T, Jodo E, Suzuki Y, Hoshino KY, Takeuchi S, Kayama Y (2009) Phencyclidine affects firing activity of basolateral amygdala neurons related to social behavior in rats. Neuroscience 159:335–343

    CAS  Article  PubMed  Google Scholar 

  • Klausberger T, Somogyi P (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321:53–57. doi:10.1126/science.1149381

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A (2005) Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 179:303–309

    CAS  Article  PubMed  Google Scholar 

  • Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI (2005) Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacology 30:1883–1894

    CAS  Article  PubMed  Google Scholar 

  • Li M-L, Hu X-Q, Li F, Gao W-J (2015) Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: still promising or a dead end? Prog Neuro-Psychopharmacol Biol Psychiatry 60:66–76. doi:10.1016/j.pnpbp.2015.02.012

    CAS  Article  Google Scholar 

  • Lindahl JS, Keifer J (2004) Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine. Neuropsychopharmacology 29:2065–2073. doi:10.1038/sj.npp.1300485

    CAS  Article  PubMed  Google Scholar 

  • Liu W, Downing ACM, Munsie LM, Chen P, Reed MR, Ruble CL, Landschulz KT, Kinon BJ, Nisenbaum LK (2012) Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia. Pharmacogenom J 12:246–254. doi:10.1038/tpj.2010.90

    CAS  Article  Google Scholar 

  • Long LE, Chesworth R, Huang X-F, Wong A, Spiro A, McGregor IS, Arnold JC, Karl T (2012) Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS ONE 7:e34129. doi:10.1371/journal.pone.0034129

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Long LE, Chesworth R, Huang X-F, McGregor IS, Arnold JC, Karl T (2013) Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence. Int J Neuropsychopharmacol 16:163–175. doi:10.1017/S1461145711001854

    CAS  Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Matosin N, Fernandez-Enright F, Frank E, Deng C, Wong J, Huang XF, Newell KA (2014) Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. J Psychiatry Neurosci 39:130242–130242

    Article  Google Scholar 

  • Mezler M, Geneste H, Gault L, Marek GJ (2010) LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr Opin Investig Drugs 11:833–845

    CAS  PubMed  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    CAS  Article  PubMed  Google Scholar 

  • Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15. doi:10.1038/npp.2011.181

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mouri A, Noda Y, Enomoto T, Nabeshima T (2007) Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int 51:173–184. doi:10.1016/j.neuint.2007.06.019

    CAS  Article  PubMed  Google Scholar 

  • Nagai T, Murai R, Matsui K, Kamei H, Noda Y, Furukawa H, Nabeshima T (2009) Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacology 202:315–328

    CAS  Article  PubMed  Google Scholar 

  • Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, Belforte JE (2012) GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62:1574–1583. doi:10.1016/j.neuropharm.2011.01.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Newell KA, Karl T, Huang XF (2013) A neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice. Neuroscience 248:670–680. doi:10.1016/j.neuroscience.2013.06.037

    CAS  Article  PubMed  Google Scholar 

  • Newell, K.A., Matosin, N., Lum, J.S., 2014. Metabotropic glutamate receptors: molecular mechanisms, role in neurological disorders and pharmacological effects, Neuroscience Research Progress. Nova Science Publishers, Inc, Hauppauge, NY.

  • O’Tuathaigh CMP, Harte M, O’Leary C, O’Sullivan GJ, Blau C, Lai D, Harvey RP, Tighe O, Fagan AJ, Kerskens C, Reynolds GP, Waddington JL (2010) Schizophrenia-related endophenotypes in heterozygous neuregulin-1 ‘knockout’ mice. Eur J Neurosci 31:349–358

    Article  PubMed  Google Scholar 

  • Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107. doi:10.1038/nm1632

    CAS  Article  PubMed  Google Scholar 

  • Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Petryshen TL, Middleton FA, Kirby A, Aldinger KA, Purcell S, Tahl AR, Morley CP, McGann L, Gentile KL, Rockwell GN, Medeiros HM, Carvalho C, Macedo A, Dourado A, Valente J, Ferreira CP, Patterson NJ, Azevedo MH, Daly MJ, Pato CN, Pato MT, Sklar P (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10(366–374):328. doi:10.1038/sj.mp.4001608

    Article  Google Scholar 

  • Pitsikas N, Markou A (2014) The metabotropic glutamate 2/3 receptor agonist LY379268 counteracted ketamine-and apomorphine-induced performance deficits in the object recognition task, but not object location task, in rats. Neuropharmacology 85:27–35. doi:10.1016/j.neuropharm.2014.05.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD (2007) In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology 193:121–136

    CAS  Article  PubMed  Google Scholar 

  • Satake S, Saitow F, Yamada J, Konishi S (2000) Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons. Nat Neurosci 3:551–558. doi:10.1038/75718

    CAS  Article  PubMed  Google Scholar 

  • Schlumberger C, Schäfer D, Barberi C, Morè L, Nagel J, Pietraszek M, Schmidt WJ, Danysz W (2009) Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav Pharmacol 20:56–66. doi:10.1097/FBP.0b013e3283242f57

    CAS  Article  PubMed  Google Scholar 

  • Spooren WP, Gasparini F, van der Putten H, Koller M, Nakanishi S, Kuhn R (2000) Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice. Eur J Pharmacol 397:R1–R2

    CAS  Article  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

    CAS  Article  PubMed  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892. doi:10.1086/342734

    Article  PubMed  PubMed Central  Google Scholar 

  • Swartz MS, Swanson JW, Hiday VA et al. (2014) Violence and severe mental illness: the effects of substance abuse and nonadherence to medication

  • Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503

    CAS  Article  PubMed  Google Scholar 

  • Thomas P, Mortensen M, Hosie AM, Smart TG (2005) Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nat Neurosci 8:889–897. doi:10.1038/nn1483

    CAS  Article  PubMed  Google Scholar 

  • Trepanier C, Lei G, Xie Y-F, MacDonald JF (2013) Group II metabotropic glutamate receptors modify N-methyl-D-aspartate receptors via Src kinase. Sci Rep 3:926. doi:10.1038/srep00926

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang C, Fridley J, Johnson KM (2005) The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. Biochem Pharmacol 69:1373–1383. doi:10.1016/j.bcp.2005.02.013

    CAS  Article  PubMed  Google Scholar 

  • Wang D, Noda Y, Zhou Y, Nitta A, Furukawa H, Nabeshima T (2007) Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission. Neuropharmacology 53:379–389. doi:10.1016/j.neuropharm.2007.05.026, S0028-3908(07)00162-1 [pii]

    CAS  Article  PubMed  Google Scholar 

  • Wang M-J, Li Y-C, Snyder MA, Wang H, Li F, Gao W-J (2013) Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons. PLoS ONE 8:e61787. doi:10.1371/journal.pone.0061787

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang X-F, Catts SV, Weickert TW (2013) Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry 18:1185–1192. doi:10.1038/mp.2012.137

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Wilkinson ST, Radhakrishnan R, D’Souza DC (2014) Impact of cannabis use on the development of psychotic disorders. Curr Addict Rep 1:115–128. doi:10.1007/s40429-014-0018-7

    Article  PubMed  PubMed Central  Google Scholar 

  • Zavitsanou K, Nguyen V, Newell K, Ballantyne P, Huang XF (2008) Rapid cortico-limbic alterations in AMPA receptor densities after administration of PCP: implications for schizophrenia. J Chem Neuroanat 36:71–76. doi:10.1016/j.jchemneu.2008.06.004

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Schizophrenia Research Institute, utilizing infrastructure funding from the NSW Ministry of Health. LY379268 was kindly gifted by Eli Lilly & Co (Indianapolis, USA). The funding bodies had no role in the study design, data collection, and publication decisions.

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Correspondence to Martin Engel.

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The Animal Ethics Committee of the University of Wollongong approved all animal and research procedures in this study, which were in agreement with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Every effort was made to minimize suffering and the number of animals used in this study.

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Engel, M., Snikeris, P., Matosin, N. et al. mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. Psychopharmacology 233, 1349–1359 (2016). https://doi.org/10.1007/s00213-016-4230-0

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  • DOI: https://doi.org/10.1007/s00213-016-4230-0

Keywords

  • mGluR2/3, LY379268, agonist, NMDA receptor, GABAA receptor, schizophrenia, neuregulin 1
  • Phencyclidine
  • Two hit
  • Antipsychotic