mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia
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.
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.
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.
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.
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.
KeywordsmGluR2/3, LY379268, agonist, NMDA receptor, GABAA receptor, schizophrenia, neuregulin 1 Phencyclidine Two hit Antipsychotic
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.
Compliance with ethical standards
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.
- 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 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 1Google Scholar
- 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 CrossRefPubMedGoogle 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
- 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
- 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar
- Karl T, Arnold JC (2014) Schizophrenia: a consequence of gene-environment interactions? Front Behav Neurosci 8Google 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 179:303–309CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 39:130242–130242CrossRefGoogle 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.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 CrossRefPubMedGoogle Scholar
- Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates. Academic, San DiegoGoogle 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 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 193:121–136CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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–R2CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- Swartz MS, Swanson JW, Hiday VA et al. (2014) Violence and severe mental illness: the effects of substance abuse and nonadherence to medicationGoogle 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]CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar