Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics

BMC Psychiatry

Natalie Matosin¹  Kelly A Newell¹ 

[1] Schizophrenia Research Institute, Darlinghurst, NSW 2010, Australia

关键词: Glutamate;    Novel antidepressant;    Novel antipsychotic;    Post-mortem human brain;    Depression;    Schizophrenia;    GRM;    mGluR5;    mGlu;    Metabotropic glutamate receptor;   

Others  :  1123811
DOI  :  10.1186/1471-244X-14-23

 received in 2013-10-02, accepted in 2014-01-21,  发布年份 2014

【 摘 要 】

Background

Pharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown.

Discussion

The majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders.

Summary

Despite the complexities, examinations of post-mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics.

【 授权许可】

   
2014 Newell and Matosin; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Matosin N, Newell KA: Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia. Neurosci Biobehav Rev 2013, 37:256-268.
• [2]Krivoy A, Fischel T, Weizman A: The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 2008, 18:395-405.
• [3]Huang C-C, Wei I-H, Huang C-L, Chen K-T, Tsai M-H, Tsai P, Tun R, Huang K-H, Chang Y-C, Lane H-Y, Tsai GE: Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry 2013, 74:734-741.
• [4]Tokita K, Yamaji T, Hashimoto K: Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol Biochem Behav 2012, 100:688-704.
• [5]Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang X-F, Catts SV, Weickert TW: Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry 2013, 18:1185-1192.
• [6]Geddes AE, Huang XF, Newell KA: Reciprocal signalling between NR2 subunits of the NMDA receptor and Neuregulin1 and their role in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011, 4:896-904.
• [7]Labrie V, Roder JC: The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev 2010, 34:351-372.
• [8]Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000, 47:351-354.
• [9]Hashimoto K, Malchow B, Falkai P, Schmitt A: Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013, 263:367-377.
• [10]Murrough JW, Wan L-B, Iacoviello B, Collins KA, Solon C, Glicksberg B, Perez AM, Mathew SJ, Charney DS, Iosifescu DV, Burdick KE: Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Psychopharmacology (Berl) 2014, 231:481-488.
• [11]Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A: Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997, 17:141-150.
• [12]Lahti AC, Koffel B, Laporte D, Tamminga CA: Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 1995, 13:9-19.
• [13]Morgan CJA, Curran HV, (iscd) the ISC on D: Ketamine use: a review. Addiction 2012, 107:27-38.
• [14]Witkin J, Marek G, Johnson B, Schoepp D: Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord - Drug Targets 2007, 6:87-100.
• [15]Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JSH, McNaughton CH, Jacobson MA, Hutson PH: Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 2009, 57:531-538.
• [16]Attucci S, Carlá V, Mannaioni G, Moroni F: Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br J Pharmacol 2001, 132:799-806.
• [17]Matosin N, Frank E, Deng C, Huang X-F, Newell KA: Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. Schizophr Res 2013, 146:170-176.
• [18]Corti C, Xuereb JH, Crepaldi L, Corsi M, Michielin F, Ferraguti F: Altered levels of glutamatergic receptors and Na+/K + ATPase-α1 in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 2011, 128:7-14.
• [19]Gupta DS, McCullumsmith RE, Beneyto M, Haroutunian V, Davis KL, Meador Woodruff JH: Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse 2005, 57:123-131.
• [20]Fatemi SH, Folsom TD, Rooney RJ, Thuras PD: mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway. Transl Psychiatry 2013, 3:e271.
• [21]Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, Burger C, Auberson YP, Sovago J, Stockmeier CA: Reduced metabotropic glutamate receptor 5 density in major depression determined by [11C] ABP688 PET and postmortem study. Am J Psychiatry 2011, 168:727-734.
• [22]Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR: Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci U S A 2004, 101:12604-12609.
• [23]El Moustaine D, Granier S, Doumazane E, Scholler P, Rahmeh R, Bron P, Mouillac B, Banères J-L, Rondard P, Pin J-P: Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc Natl Acad Sci U S A 2012, 109:16342-16347.
• [24]Romano C, Yang W-L, O’Malley KL: Metabotropic glutamate receptor 5 Is a disulfide-linked dimer. J Biol Chem 1996, 271:28612-28616.
• [25]Corti C, Crepaldi L, Mion S, Roth AL, Xuereb JH, Ferraguti F: Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia. Biol Psychiatry 2007, 62:747-755.
• [26]Wootten D, Christopoulos A, Sexton PM: Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 2013, 12:630-644.
• [27]O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr: A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in Rat forebrain. J Pharmacol Exp Ther 2004, 309:568-577.
• [28]Rodriguez AL, Zhou Y, Williams R, David Weaver C, Vinson PN, Dawson ES, Steckler T, Lavreysen H, Mackie C, Bartolomé JM, Macdonald GJ, Scott Daniels J, Niswender CM, Jones CK, Jeffrey Conn P, Lindsley CW, Stauffer SR: Discovery and SAR of a novel series of non-MPEP site mGlu₅ PAMs based on an aryl glycine sulfonamide scaffold. Bioorg Med Chem Lett 2012, 22:7388-7392.
• [29]Hammond AS, Rodriguez AL, Townsend SD, Niswender CM, Gregory KJ, Lindsley CW, Conn PJ: Discovery of a novel chemical class of mGlu 5 allosteric ligands with distinct modes of pharmacology. ACS Chem Neurosci 2010, 1:702-716.
• [30]Greenbaum D, Colangelo C, Williams K, Gerstein M: Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003, 4:117. BioMed Central Full Text
• [31]Ohnuma T, Tessler S, Arai H, Faull RLM, McKenna PJ, Emson PC: Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Mol Brain Res 2000, 85:24-31.
• [32]Richardson-Burns SM, Haroutunian V, Davis KL, Watson SJ, Meador-Woodruff JH: Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus. Biol Psychiatry 2000, 47:22-28.
• [33]Volk DW, Eggan SM, Lewis DA: Alterations in metabotropic glutamate receptor 1a and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry 2010, 167:1489-1498.
• [34]Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC: Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Mol Brain Res 1998, 56:207-217.
• [35]Lewis DA, Glantz LA, Pierri JN, Sweet RA: Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons. Ann N Y Acad Sci 2003, 1003:102-112.
• [36]Malherbe P, Kew JNC, Richards JG, Knoflach F, Kratzeisen C, Zenner M-T, Faull RLM, Kemp JA, Mutel V: Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum. Mol Brain Res 2002, 109:168-178.
• [37]Mion S, Corti C, Neki A, Shigemoto R, Corsi M, Fumagalli G, Ferraguti F: Bidirectional regulation of neurite elaboration by alternatively spliced metabotropic glutamate receptor 5 (mGluR5) isoforms. Mol Cell Neurosci 2001, 17:957-972.
• [38]Wang H, Westin L, Nong Y, Birnbaum S, Bendor J, Brismar H, Nestler E, Aperia A, Flajolet M, Greengard P: Norbin is an endogenous regulator of metabotropic glutamate receptor 5 signaling. Science 2009, 326:1554-1557.
• [39]Szumlinski KK, Lominac KD, Kleschen MJ, Oleson EB, Dehoff MH, Schwarz MK, Schwartz MK, Seeburg PH, Seeberg PH, Worley PF, Kalivas PW: Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia. Genes Brain Behav 2005, 4:273-288.
• [40]Timms AE, Dorschner MO, Wechsler J, Choi KY, Kirkwood R, Girirajan S, Baker C, Eichler EE, Korvatska O, Roche KW, Horwitz MS, Tsuang DW: Support for the N -methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry 2013, 70:582-590.
• [41]Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, Winiger E, Breier A, Shekhar A, Amdur R, Koller D, Nurnberger JI, Corvin A, Geyer M, Tsuang MT, Salomon D, Schork NJ, Fanous AH, O’Donovan MC, Niculescu AB: Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012, 17:887-905.
• [42]Gray L, van den Buuse M, Scarr E, Dean B, Hannan AJ: 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 2009, 12:45-60.
• [43]Rietschel M, Mattheisen M, Frank J, Treutlein J, Degenhardt F, Breuer R, Steffens M, Mier D, Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Herms S, Wichmann H-E, Schreiber S, Jöckel K-H, Strohmaier J, Roeske D, Haenisch B, Gross M, Hoefels S, Lucae S, Binder EB, Wienker TF, Schulze TG, Schmäl C, Zimmer A, Juraeva D, Brors B, et al.: Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol Psychiatry 2010, 68:578-585.
• [44]Gregory KJ, Herman EJ, Ramsey AJ, Hammond AS, Byun NE, Stauffer SR, Manka JT, Jadhav S, Bridges TM, Weaver CD, Niswender CM, Steckler T, Drinkenburg WH, Ahnaou A, Lavreysen H, Macdonald GJ, Bartolomé JM, Mackie C, Hrupka BJ, Caron MG, Daigle TL, Lindsley CW, Conn PJ, Jones CK: N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. J Pharmacol Exp Ther 2013, 347:438-457.
• [45]Gastambide F, Gilmour G, Robbins TW, Tricklebank MD: The mGlu₅ positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat. Neuropharmacology 2013, 64:240-247.
• [46]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: In vitro characterisation 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. Neuropharmacology 2013, 64:224-239.
• [47]Rodriguez AL, Grier MD, Jones CK, Herman EJ, Kane AS, Smith RL, Williams R, Zhou Y, Marlo JE, Days EL, Blatt TN, Jadhav S, Menon UN, Vinson PN, Rook JM, Stauffer SR, Niswender CM, Lindsley CW, Weaver CD, Conn PJ: Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol 2010, 78:1105-1123.
• [48]Liu CY, Jiang XX, Zhu YH, Wei DN: Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: Role of brain-derived neurotrophic factor. Neuroscience 2012, 223:219-224.
• [49]Tatarczyńska E, Klodzińska A, Chojnacka-Wójcik E, Palucha A, Gasparini F, Kuhn R, Pilc A: Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001, 132:1423-1430.
• [50]Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY: Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 2007, 17:172-179.
• [51]Pietraszek M, Gravius A, Schäfer D, Weil T, Trifanova D, Danysz W: mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 2005, 49:73-85.
• [52]Li X, Need AB, Baez M, Witkin JM: Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 2006, 319:254-259.
• [53]Hashimoto K, Sawa A, Iyo M: Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 2007, 62:1310-1316.
• [54]Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF: Subtype-specific alterations of aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004, 61:705-713.
• [55]Hashimoto K: Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 2009, 61:105-123.
• [56]Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP: Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 2005, 49:1053-1066.
• [57]Pop AS, Gomez-Mancilla B, Neri G, Willemsen R, Gasparini F: Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacology (Berl)in press
• [58]Palucha A, Pilc A: Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther 2007, 115:116-147.
• [59]Pecknold JC, McCLURE DJ, Appeltauer L, Wrzesinski L, Allan T: Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 1982, 2:129-133.
• [60]Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R: A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 2009, 46:266-271.
• [61]Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, Ramos FJ, Cornish K, He Y, Paulding C, Neri G, Chen F, Hadjikhani N, Martinet D, Meyer J, Beckmann JS, Delange K, Brun A, Bussy G, Gasparini F, Hilse T, Floesser A, Branson J, Bilbe G, Johns D, Gomez-Mancilla B: Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 2011, 3:64ra1.
• [62]Emmitte KA: mGlu 5 negative allosteric modulators: a patent review (2010–2012). Expert Opin Ther Pat 2013, 23:393-408.
• [63]Newell KA: Metabotropic glutamate receptor 5 in schizophrenia: emerging evidence for the development of antipsychotic drugs. Future Med Chem 2013, 5:1471-1474.