Epigenetic Modulation of Reelin Function in Schizophrenia and Bipolar Disorder

  • Hamid Mostafavi Abdolmaleky
  • Cassandra L. Smith
  • Jin-Rong Zhou
  • Sam Thiagalingam

Studies from several laboratories have provided convincing data to support the notion that altered DNA methylation in response to varying physiological and environmental conditions may play a critical role in the fine-tuning of gene expression. However, the establishment of abnormal gene promoter DNA methylation patterns resulting from environmental insults or dysfunctional genes of the DNA methylation machinery may destabilize the normal epigenetic modification of genes. This may affect the equilibrium in the differential gene expression patterns in the normal differentiated cells and tilt the balance toward the disease phenotype. The individuals with genetic susceptibility to specific diseases are likely to be more prone to abnormal DNA methylation. Thus, it is highly likely that the lack of a direct relationship between genotype and phenotype in major psychiatric disorders and the variability in the manifestation of diseases in individuals with identical genetic makeup could be derived from the changes in the DNA methylation patterns.


Promoter Methylation Rett Syndrome Epigenetic Modulation Bipolar Disorder Patient Reeler Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdolmaleky, H. M., Smith, C. L., Faraone, S. V., Shafa, R., Stone, W., Glatt, S. J., and Tsuang, M. T. (2004a). Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am. J. Med. Genet. 127B (1): 51-59.CrossRefPubMedGoogle Scholar
  2. Abdolmaleky, H. M., Faraone, S. V., Glatt, S. J., and Tsuang, M. T. (2004b). Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr. Res. 67 (1): 53-62.CrossRefPubMedGoogle Scholar
  3. Abdolmaleky, H. M., Cheng, H. H., Russo, A., Smith, C. L., Faraone, S. V., Shafa, R., Wilcox, M., Glatt, S., Stone, W. S., Nguyen, G., Ponte, J. F., Thiagalingam, S., and Tsuang, M. (2005). Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a pre-liminary report. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B: 60-66.CrossRefPubMedGoogle Scholar
  4. Abdolmaleky, H. M., Cheng, K. H., Faraone, S. V., Wilcox, M., Glatt, S. J., Gao, F., Smith, C. L., Shafa, R., Aeali, B., Carnevale, J., Pan, H., Papageorgis, P., Ponte, J. F., Sivaraman, V., Tsuang, M. T., and Thiagalingam, S. (2006). Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum. Mol. Genet. 15 (21): 3132-3145.CrossRefPubMedGoogle Scholar
  5. Abdolmaleky, H. M., Smith, C. L., Zhou, R. J., Thiagalingam, S. (2008). “Epigenetic alterations of the dopaminergic system in major psychiatric disorders” in Pharmacogenomics in drug dis-covery and development, Yan, Q., Humana Press. London, U.K. 187-212.CrossRefGoogle Scholar
  6. Akahane, A., Kunugi, H., Tanaka, H., and Nanko, S. (2002). Association analysis of polymorphic CGG repeat in 5′ UTR of the reelin and VLDLR genes with schizophrenia. Schizophr. Res. 58 (1): 37-41.CrossRefPubMedGoogle Scholar
  7. Akbarian, S. (2003). The neurobiology of Rett syndrome. Neuroscientist. 9 (1): 57-63.CrossRefPubMedGoogle Scholar
  8. Akbarian, S., Jiang, Y., and Laforet, G. (2006). The molecular pathology of Rett syndrome: syn-opsis and update. Neuromol. Med. 8 (4): 485-494.CrossRefGoogle Scholar
  9. Ballmaier, M., Zoli, M., Leo, G., Agnati, L. F., and Spano, P. (2002). Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. Eur. J. Neurosci. 15 (7): 1197-1205.CrossRefPubMedGoogle Scholar
  10. Beffert, U., Weeber, E. J., Durudas, A., Qiu, S., Masiulis, I., Sweatt, J. D., Li, W. P., Adelmann, G., Frotscher, M., Hammer, R. E., and Herz, J. (2005). Modulation of synaptic plasticity and memory by reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47 (4): 567-579.CrossRefPubMedGoogle Scholar
  11. Beffert, U., Durudas, A., Weeber, E. J., Stolt, P. C., Giehl, K. M., Sweatt, J. D., Hammer, R. E., and Herz, J. (2006). Functional dissection of reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J. Neurosci. 26 (7): 2041-2052.CrossRefPubMedGoogle Scholar
  12. Bertino, L., Ruffini, M. C., Copani, A., Bruno, V., Raciti, G., Cambria, A., and Nicoletti, F. (1996). Growth conditions influence DNA methylation in cultured cerebellar granule cells. Dev. Brain Res. 95: 38-43.CrossRefGoogle Scholar
  13. Bestor, T. H. (2000). The DNA methyltransferases of mammals. Hum. Mol. Genet. 9: 2395-2402.CrossRefPubMedGoogle Scholar
  14. Bird, A. (2002). DNA methylation patterns and epigenetic memory. Genes Dev. 16: 6-21.CrossRefPubMedGoogle Scholar
  15. Bleich, S., Lenz, B., Ziegenbein, M., Beutler, S., Frieling, H., Kornhuber, J., and Bonsch, D. (2006). Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcohol. Clin. Exp. Res. 30: 587-591.CrossRefPubMedGoogle Scholar
  16. Bonsch, D., Lenz, B., Kornhuber, J., and Bleich, S. (2005). DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport 16: 167-170.CrossRefPubMedGoogle Scholar
  17. Chan, M. W., Chu, E. S., To, K. F., and Leung, W. K. (2004). Quantitative detection of methylated SOCS-1, a tumor suppressor gene, by a modified protocol of quantitative real time methyla-tion-specific PCR using SYBR green and its use in early gastric cancer detection. Biotechnol. Lett. 26: 1289-1293.CrossRefPubMedGoogle Scholar
  18. Chen, Y., Sharma, R. P., Costa, R. H., Costa, E., and Grayson, D. R. (2002). On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res. 30: 2930-2939.CrossRefPubMedGoogle Scholar
  19. Chen, Y., Beffert, U., Ertunc, M., Tang, T. S., Kavalali, E. T., Bezprozvanny, I., and Herz, J. (2005). Reelin modulates NMDA receptor activity in cortical neurons. J. Neurosci. 25 (36): 8209-8216.CrossRefPubMedGoogle Scholar
  20. Cooney, C. A., Dave, A. A., Wolff, G. L. (2002). Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 132: 2393-2400S.Google Scholar
  21. Costa, E., Davis, J., Grayson, D. R., Guidotti, A., Pappas, G. D., and Pesold, C. (2001). Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vul-nerability. Neurobiol. Dis. 8: 723-742.CrossRefPubMedGoogle Scholar
  22. Costa, E., Dong, E., Grayson, D. R., Ruzicka, W. B., Simonini, M. V., Veldic, M., and Guidotti, A. (2006). Epigenetic targets in GABAergic neurons to treat schizophrenia. Adv. Pharmacol. 54: 95-117.CrossRefPubMedGoogle Scholar
  23. Costello, J. F., and Plass, C. (2001). Methylation matters. J. Med. Genet. 38 (5): 285-303.CrossRefPubMedGoogle Scholar
  24. Davies, R., and Morris, B. (1997). Molecular Biology of Neuron. Oxford University Press, London.Google Scholar
  25. Dong, E., Agis-Balboa, R. C., Simonini, M. V., Grayson, D. R., Costa, E., and Guidotti, A. (2005). Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc. Natl. Acad. Sci. USA 102 (35): 12578-12583.CrossRefPubMedGoogle Scholar
  26. Eastwood, S. L., and Harrison, P. J. (2003). Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and mor-phologic aspects of the neurodevelopmental hypothesis. Mol. Psychiatry 8 (9): 769, 821-831.Google Scholar
  27. Fackler, M. J., McVeigh, M., Mehrotra, J., Blum, M. A., Lange, J., Lapides, A., Garrett, E., Argani, P., and Sukumar, S. (2004). Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res. 64: 4442-4452.CrossRefPubMedGoogle Scholar
  28. Fatemi, S. H., Earle, J. A., and McMenomy, T. (2000). Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol. Psychiatry 5: 654-663.CrossRefPubMedGoogle Scholar
  29. Fatemi, S. H., Stary, J. M., Araghi-Niknam, M., and Egan, E. (2005a). GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of reelin and GAD 65 & 67 kDa proteins in cerebellum. Schizophr. Res. 72: 109-122.CrossRefPubMedGoogle Scholar
  30. Fatemi, S. H., Snow, A. V., Stary, J. M., Araghi-Niknam, M., Reutiman, T. J., Lee, S., Brooks, A.I., and Pearce, D.A. (2005b). Reelin signaling is impaired in autism. Biol. Psychiatry 57: 777-787.CrossRefPubMedGoogle Scholar
  31. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Bell, C., Nos, L., Fried, P., Pearce, D. A., Singh, S., Siderovski, D. P., Willard, F. S., and Fukuda, M. (2006). Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray tech-nique. Neuropsychopharmacology 31 (9): 1888-1899.CrossRefPubMedGoogle Scholar
  32. Fenech, M. (2001). The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat. Res. 475: 57-67.PubMedGoogle Scholar
  33. Frommer, M., McDonald, L. E., Millar, D. S., Collis, C. M., Watt, F., Grigg, G. W., Molloy, P. L., and Paul, C. L. (1992). A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl. Acad. Sci. USA 89 (5): 1827-1831.CrossRefPubMedGoogle Scholar
  34. Goldberger, C., Gourion, D., Leroy, S., Schurhoff, F., Bourdel, M. C., Leboyer, M., and Krebs, M. O. (2005). Population-based and family-based association study of 5′UTR polymorphism of the reelin gene and schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 137 (1): 51-55.Google Scholar
  35. Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., and Costa, E. (2005). Reelin promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. USA 102 (26): 9341-9346.CrossRefPubMedGoogle Scholar
  36. Guidotti, A., Auta, J., Davis, J. M., Di-Giorgi-Gerevini, V., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey, G., Pesold, C., Sharma, R., Uzunov, D., and Costa, E. (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch. Gen. Psychiatry 57 (11): 1061-1069.CrossRefPubMedGoogle Scholar
  37. Guidotti, A., Ruzicka, W., Grayson, D. R., Veldic, M., Pinna, G., Davis, J. M., and Costa, E. (2007). S-adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psy-chosis. Neuroreport 18 (1): 57-60.CrossRefPubMedGoogle Scholar
  38. Herman, J. G., Graff, J. R., Myohanen, S., Nelkin, B. D., and Baylin, S. B. (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA 93 (18): 9821-9826.CrossRefPubMedGoogle Scholar
  39. Homayouni, R., Magdaleno, S., Keshvara, L., Rice, D. S., and Curran, T. (2003). Interaction of disabled-1 and the GTPase activating protein Dab2IP in mouse brain. Brain Res. Mol. Brain Res. 115 (2): 121-129.CrossRefPubMedGoogle Scholar
  40. Huang, C. H., and Chen, C. H. (2006). Absence of association of a polymorphic GGC repeat at the 5’ untranslated region of the reelin gene with schizophrenia. Psychiatry Res. 142 (1): 89-92.CrossRefPubMedGoogle Scholar
  41. Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D.P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P., and Costa, E. (1998). A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl. Acad. Sci. USA 95 (26): 15718-15723.CrossRefPubMedGoogle Scholar
  42. Iwamoto, K., Bundo, M., Yamada, K., Takao, H., Iwayama-Shigeno, Y., Yoshikawa, T., and Kato, T. (2005). DNA methylation status of SOX10 correlates with its downregulation and oli-godendrocyte dysfunction in schizophrenia. J. Neurosci. 25 (22): 5376-5381.CrossRefPubMedGoogle Scholar
  43. Jiang, Y. H., Bressler, J., and Beaudet, A. L. (2004). Epigenetics and human disease. Annu. Rev. Genomics Hum. Genet. 5: 479-510.CrossRefPubMedGoogle Scholar
  44. Kaludov, N. K., and Wolffe, A. P. (2000). MeCP2 driven transcriptional repression in vitro: selec-tivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res. 28 (9): 1921-1928.CrossRefPubMedGoogle Scholar
  45. Kim, G. D., Ni, J., Kelesoglu, N., Roberts, R. J., and Pradhan, S. (2002). Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltrans-ferases. EMBO J. 21 (15): 4183-4195.CrossRefPubMedGoogle Scholar
  46. Lavorgna, G., Dahary, D., Lehner, B., Sorek, R., Sanderson, C. M., and Casari, G. (2004). In search of antisense. Trends Biochem. Sci. 29 (2): 88-94.CrossRefPubMedGoogle Scholar
  47. Levenson, J. M., O’Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., and Sweatt, J. D. (2004). Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 79 (39): 40545-40559.CrossRefGoogle Scholar
  48. Marrone, M. C., Marinelli, S., Biamonte, F., Keller, F., Sgobio, C. A., Ammassari-Teule, M., Bernardi, G., and Mercuri, N. B. (2006). Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Eur. J. Neurosci. 24 (7): 2061-2070.CrossRefPubMedGoogle Scholar
  49. Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., and Sun, Y. E. (2003). DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302 (5646): 890-893.CrossRefPubMedGoogle Scholar
  50. Martucci, L., Wong, A. H., Trakalo, J., Cate-Carter, T., Wong, G. W., Macciardi, F. M., and Kennedy, J. L. (2003). N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. Am. J. Med. Genet. B Neuropsychiatr. Genet. 119 (1): 24-27.CrossRefGoogle Scholar
  51. Monk, M. (1995). Epigenetic programming of differential gene expression in development and evolution. Dev. Genet. 17 (3): 188-197.CrossRefPubMedGoogle Scholar
  52. Morange, M. (2002). The relations between genetics and epigenetics: a historical point of view. Ann. N.Y. Acad. Sci. 981: 50-60.PubMedCrossRefGoogle Scholar
  53. Murphy, B. C., O’Reilly, R. L., and Singh, S. M. (2005). Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 133 (1): 37-42.Google Scholar
  54. Nishikawa, S., Goto, S., Yamada, K., Hamasaki, T., and Ushio, Y. (2003). Lack of reelin causes malpositioning of nigral dopaminergic neurons: evidence from comparison of normal and Reln(rl) mutant mice. J. Comp. Neurol. 461: 166-173.CrossRefPubMedGoogle Scholar
  55. Park-Sarge, O. K., and Sarge, K. D. (1995). Cis-regulatory elements conferring cyclic 3′,5′-adeno-sine monophosphate responsiveness of the progesterone receptor gene in transfected rat granulosa cells. Endocrinology 136 (12): 5430-5437.CrossRefPubMedGoogle Scholar
  56. Persico, A. M., Levitt, P., and Pimenta, A. F. (2006). Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J. Neural Transm. 113 (10): 1373-1382.CrossRefPubMedGoogle Scholar
  57. Pesold, C., Liu, W. S., Guidotti, A., Costa, E., and Caruncho, H. J. (1999). Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression. Proc. Natl. Acad. Sci. USA 96 (6): 3217-3222.CrossRefPubMedGoogle Scholar
  58. Petronis, A. (2000). The genes for major psychosis: aberrant sequence or regulation? Neuropsychopharmacology 23: 1-12.CrossRefPubMedGoogle Scholar
  59. Popendikyte, V., Laurinavicius, A., Paterson, A. D., Macciardi, F., Kennedy, J. L., and Petronis, A. (1999). DNA methylation at the putative promoter region of the human dopamine D2 receptor gene. Neuroreport 10 (6): 1249-1255.CrossRefPubMedGoogle Scholar
  60. Robertson, K. D., and Wolffe, A. P. (2000). DNA methylation in health and disease. Nature Rev. Genet. 1 (1): 11-19.CrossRefPubMedGoogle Scholar
  61. Russo, V., Martienssen, R., and Riggs, A. (1996). Epigenetic Mechanisms of Gene Regulation. Cold Spring Harbor Laboratory Press, Plainview, NY.Google Scholar
  62. Ruzicka, W. B., Zhubi, A., Veldic, M., Grayson, D. R., Costa, E., and Guidotti, A. (2007). Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection. Mol. Psychiatry 12 (4): 385-397.CrossRefPubMedGoogle Scholar
  63. Singh, S. M., Murphy, B., and O’Reilly, R. L. (2003). Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia. Clin. Genet. 64 (6): 451-460.CrossRefPubMedGoogle Scholar
  64. Swift-Scanlan, T., Blackford, A., Argani, P., Sukumar, S., and Fackler, M. J. (2006). Two-color quantitative multiplex methylation-specific PCR. Biotechniques 40: 210-219.CrossRefPubMedGoogle Scholar
  65. Tamura, Y., Kunugi, H., Ohashi, J., and Hohjoh, H. (2007). Epigenetic aberration of the human REELIN gene in psychiatric disorders. Mol. Psychiatry 12: 519.CrossRefPubMedGoogle Scholar
  66. Tasman, A., Key, J., and Lieberman, J. A. (1997). Psychiatry. W. B. Saunders, Philadelphia.Google Scholar
  67. Tremolizzo, L., Carboni, G., Ruzicka, W. B., Mitchell, C. P., Sugaya, I., Tueting, P., Sharma, R., Grayson, D. R., Costa, E., and Guidotti, A. (2002). An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl. Acad. Sci. USA 99 (26): 17095-17100.CrossRefPubMedGoogle Scholar
  68. Veldic, M., Caruncho, H. J., Liu, W. S., Davis, J., Satta, R., Grayson, D. R., Guidotti, A., and Costa, E. (2004). DNA-methyltransferase 1 mRNA is selectively overexpressed in telen-cephalic GABAergic interneurons of schizophrenia brains. Proc. Natl. Acad. Sci. USA 101 (1): 348-353.CrossRefPubMedGoogle Scholar
  69. Veldic, M., Kadriu, B., Maloku, E., Agis-Balboa, R. C., Guidotti, A., Davis, J. M., and Costa, E. (2007). Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophr. Res. 91 (1-3): 51-61.CrossRefPubMedGoogle Scholar
  70. Waterland, R. A., Lin, J. R., Smith, C. A., and Jirtle, R. L. (2006). Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum. Mol. Genet. 15: 705-716.CrossRefPubMedGoogle Scholar
  71. Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., and Meaney, M. J. (2004). Epigenetic programming by maternal behavior. Nature Neurosci. 8: 847-854.CrossRefGoogle Scholar
  72. Weaver, I. C., Champagne, F. A., Brown, S. E., Dymov, S., Sharma, S., Meaney, M. J., and Szyf, M. (2005). Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci. 25 (47): 11045-11054.CrossRefPubMedGoogle Scholar
  73. Weinhausel, A., and Haas, O. A. (2001). Evaluation of the fragile X (FRAXA) syndrome with methylation-sensitive PCR. Hum. Genet. 108 (6): 450-458.CrossRefPubMedGoogle Scholar
  74. Williams, J., McGuffin, P., Nothen, M., and Owen, M. J. (1997). Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 349 (9060): 1221.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Hamid Mostafavi Abdolmaleky
    • 1
    • 2
    • 3
    • 4
  • Cassandra L. Smith
    • 1
  • Jin-Rong Zhou
    • 2
  • Sam Thiagalingam
    • 3
  1. 1.Biomedical Engineering DepartmentBoston UniversityBoston
  2. 2.Laboratory of Nutrition and Metabolism at BIDMC, Department of SurgeryHarvard Medical SchoolBoston
  3. 3.Departments of Medicine (Genetics Program), Genetics & Genomics, and Pathology & Laboratory MedicineBoston University School of MedicineBoston
  4. 4.Department of Psychiatry, Tehran Psychiatric Institute and Mental Health Research CenterIran University of Medical SciencesTehranIran

Personalised recommendations