A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia
Tóm tắt
Pre-mRNAs of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid (AMPA)/kainate glutamate receptors undergo post-transcriptional modification known as RNA editing that is mediated by adenosine deaminase acting on RNA type 2 (ADAR2). This modification alters the amino acid sequence and function of the receptor. Glutamatergic signaling has been suggested to have a role in mood disorders and schizophrenia, but it is unknown whether altered RNA editing of AMPA/kainate receptors has pathophysiological significance in these mental disorders. In this study, we found that ADAR2 expression tended to be decreased in the postmortem brains of patients with schizophrenia and bipolar disorder. Decreased ADAR2 expression was significantly correlated with decreased editing of the R/G sites of AMPA receptors. In heterozygous Adar2 knockout mice (Adar2+/− mice), editing of the R/G sites of AMPA receptors was decreased. Adar2+/− mice showed a tendency of increased activity in the open-field test and a tendency of resistance to immobility in the forced swimming test. They also showed enhanced amphetamine-induced hyperactivity. There was no significant difference in amphetamine-induced hyperactivity between Adar2+/− and wild type mice after the treatment with an AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline. These findings collectively suggest that altered RNA editing efficiency of AMPA receptors due to down-regulation of ADAR2 has a possible role in the pathophysiology of mental disorders.
Tài liệu tham khảo
Neurobiology of Mental Illness. Edited by: Charney D, Nestler S, Eric J. 2011, New York: Oxford University Press
Javitt DC: Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 2010, 47: 4-16.
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006, 63: 856-864. 10.1001/archpsyc.63.8.856.
Iwamoto K, Bundo M, Kato T: Serotonin receptor 2C and mental disorders: genetic, expression and RNA editing studies. RNA Biol. 2009, 6: 248-253. 10.4161/rna.6.3.8370.
Barbon A, Barlati S: Glutamate receptor RNA editing in health and disease. Biochemistry (Mosc). 2011, 76: 882-889. 10.1134/S0006297911080037.
Silberberg G, Lundin D, Navon R, Ohman M: Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum Mol Genet. 2012, 21: 311-321. 10.1093/hmg/ddr461.
Lomeli H, Mosbacher J, Melcher T, Hoger T, Geiger JR, Kuner T, Monyer H, Higuchi M, Bach A, Seeburg PH: Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science. 1994, 266: 1709-1713. 10.1126/science.7992055.
Dracheva S, Elhakem SL, Marcus SM, Siever LJ, McGurk SR, Haroutunian V: RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia. J Neurochem. 2003, 87: 1402-1412. 10.1046/j.1471-4159.2003.02115.x.
Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E: RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology. 2001, 24: 478-491. 10.1016/S0893-133X(00)00223-2.
Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V: Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. Mol Psychiatry. 2008, 13: 1001-1010. 10.1038/sj.mp.4002081.
Zhu H, Urban DJ, Blashka J, McPheeters MT, Kroeze WK, Mieczkowski P, Overholser JC, Jurjus GJ, Dieter L, Mahajan GJ, Rajkowska G, Wang Z, Sullivan PF, Stockmeier CA, Roth BL: Quantitative analysis of focused a-to-I RNA editing sites by ultra-high-throughput sequencing in psychiatric disorders. PLoS One. 2012, 7: e43227-10.1371/journal.pone.0043227.
Iwamoto K, Kato T: RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci Lett. 2003, 346: 169-172. 10.1016/S0304-3940(03)00608-6.
Sodhi MS, Burnet PW, Makoff AJ, Kerwin RW, Harrison PJ: RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia. Mol Psychiatry. 2001, 6: 373-379. 10.1038/sj.mp.4000920.
Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C: Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron. 2002, 34: 349-356. 10.1016/S0896-6273(02)00660-8.
Lyddon R, Dwork AJ, Keddache M, Siever LJ, Dracheva S: Serotonin 2c receptor RNA editing in major depression and suicide. World J Biol Psychiatry. 2012, 14: 590-601.
Akbarian S, Smith MA, Jones EG: Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer’s disease, Huntington’s disease and schizophrenia. Brain Res. 1995, 699: 297-304. 10.1016/0006-8993(95)00922-D.
Lyddon R, Navarrett S, Dracheva S: Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder. J Psychiatry Neurosci. 2012, 37: 267-272. 10.1503/jpn.110107.
Sanacora G, Treccani G, Popoli M: Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012, 62: 63-77. 10.1016/j.neuropharm.2011.07.036.
Tomita H, Vawter MP, Walsh DM, Evans SJ, Choudary PV, Li J, Overman KM, Atz ME, Myers RM, Jones EG, Watson SJ, Akil H, Bunney WE: Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain. Biol Psychiatry. 2004, 55: 346-352. 10.1016/j.biopsych.2003.10.013.
Iwamoto K, Bundo M, Kato T: Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet. 2005, 14: 241-253.
Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH: Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 2000, 406: 78-81. 10.1038/35017558.
Wolf ME: The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol. 1998, 54: 679-720. 10.1016/S0301-0082(97)00090-7.
Reid MS, Hsu K, Berger SP: Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine. Synapse. 1997, 27: 95-105. 10.1002/(SICI)1098-2396(199710)27:2<95::AID-SYN1>3.0.CO;2-6.
Li Y, Vartanian AJ, White FJ, Xue CJ, Wolf ME: Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine. Psychopharmacology (Berl). 1997, 134: 266-276. 10.1007/s002130050449.
Vanover KE: Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice. Psychopharmacology (Berl). 1998, 136: 123-131. 10.1007/s002130050547.
Simmons M, Meador-Woodruff JH, Sodhi MS: Increased cortical expression of an RNA editing enzyme occurs in major depressive suicide victims. Neuroreport. 2010, 21: 993-997.
Kawahara Y, Ito K, Ito M, Tsuji S, Kwak S: Novel splice variants of human ADAR2 mRNA: skipping of the exon encoding the dsRNA-binding domains, and multiple C-terminal splice sites. Gene. 2005, 363: 193-201.
Tariq A, Garncarz W, Handl C, Balik A, Pusch O, Jantsch MF: RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation. Nucleic Acids Res. 2013, 41: 2581-2593. 10.1093/nar/gks1353.
Kubota M, Kasahara T, Iwamoto K, Komori A, Ishiwata M, Miyauchi T, Kato T: Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder. Int J Neuropsychopharmacol. 2010, 13: 1355-1368. 10.1017/S1461145710000362.
Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, Cheung VG: Widespread RNA and DNA sequence differences in the human transcriptome. Science. 2011, 333: 53-58. 10.1126/science.1207018.
Ju YS, Kim JI, Kim S, Hong D, Park H, Shin JY, Lee S, Lee WC, Yu SB, Park SS, Seo SH, Yun JY, Kim HJ, Lee DS, Yavartanoo M, Kang HP, Gokcumen O, Govindaraju DR, Jung JH, Chong H, Yang KS, Kim H, Lee C, Seo JS: Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals. Nat Genet. 2011, 43: 745-752. 10.1038/ng.872.
Bahn JH, Lee JH, Li G, Greer C, Peng G, Xiao X: Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res. 2012, 22: 142-150. 10.1101/gr.124107.111.
Peng Z, Cheng Y, Tan BC, Kang L, Tian Z, Zhu Y, Zhang W, Liang Y, Hu X, Tan X, Guo J, Dong Z, Bao L, Wang J: Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol. 2012, 30: 253-260. 10.1038/nbt.2122.
Ramaswami G, Lin W, Piskol R, Tan MH, Davis C, Li JB: Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods. 2012, 9: 579-581. 10.1038/nmeth.1982.
Schrider DR, Gout JF, Hahn MW: Very few RNA and DNA sequence differences in the human transcriptome. PLoS One. 2011, 6: e25842-10.1371/journal.pone.0025842.
Picardi E, Gallo A, Galeano F, Tomaselli S, Pesole G: A novel computational strategy to identify A-to-I RNA editing sites by RNA-Seq data: de novo detection in human spinal cord tissue. PLoS One. 2012, 7: e44184-10.1371/journal.pone.0044184.
Horsch M, Seeburg PH, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Garrett L, Gotz A, Hans W, Higuchi M, Holter SM, Naton B, Prehn C, Puk O, Racz I, Rathkolb B, Rozman J, Schrewe A, Adamski J, Busch DH, Esposito I, Graw J, Ivandic B, Klingenspor M, Klopstock T, Mempel M, Ollert M, Schulz H, Wolf E, Wurst W, et al: Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice. J Biol Chem. 2011, 286: 18614-18622. 10.1074/jbc.M110.200881.
Singh M, Zimmerman MB, Beltz TG, Johnson AK: Affect-related behaviors in mice misexpressing the RNA editing enzyme ADAR2. Physiol Behav. 2009, 97: 446-454. 10.1016/j.physbeh.2009.03.029.
Singh M, Singh MM, Na E, Agassandian K, Zimmerman MB, Johnson AK: Altered ADAR 2 equilibrium and 5HT(2C) R editing in the prefrontal cortex of ADAR 2 transgenic mice. Genes Brain Behav. 2011, 10: 637-647. 10.1111/j.1601-183X.2011.00701.x.
Torrey EF, Webster M, Knable M, Johnston N, Yolken RH: The stanley foundation brain collection and neuropathology consortium. Schizophr Res. 2000, 44: 151-155. 10.1016/S0920-9964(99)00192-9.
Association AP: Diagnostic and Statistical Manual of Mental Disorders. 1994, Arlington, VA: American Psychiatric Publishing, 4
Iwamoto K, Kato T: Effects of cocaine and reserpine administration on RNA editing of rat 5-HT2C receptor estimated by primer extension combined with denaturing high-performance liquid chromatography. Pharmacogenomics J. 2002, 2: 335-340. 10.1038/sj.tpj.6500130.
Iwamoto K, Bundo M, Kato T: Estimating RNA editing efficiency of five editing sites in the serotonin 2C receptor by pyrosequencing. RNA. 2005, 11: 1596-1603. 10.1261/rna.2114505.