Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders

Frontiers in Cellular Neuroscience

Volumn 10, Issue APR, 2016, Pages

  Guidotti, Alessandro ^a   Grayson, Dennis R ^a   Caruncho, Hector J ^b  

^a UNIVERSITY OF ILLINOIS   (United States)

^b UNIVERSITY OF SASKATCHEWAN   (Canada)

Author keywords

Bipolar disorder; Dab1; Promoter methylation; RELN; Schizophrenia; Synaptic plasticity

Indexed keywords

BINDING PROTEIN; DNA METHYLTRANSFERASE; METHIONINE; REELIN; S ADENOSYLMETHIONINE;

BIPOLAR DISORDER; COGNITIVE DEFECT; DNA METHYLATION; DOWN REGULATION; ENVIRONMENTAL FACTOR; GENE EXPRESSION; GENE MUTATION; NERVE CELL PLASTICITY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 84963756166     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2016.00089     Document Type: Review

References (105)

1. Abdolmaleky, H. M., Cheng, K. H., Russo, A., Smith, C. L., Faraone, S. V., Wilcox, M., et al. (2005). Hypermethylation of the reelin (Reelin) promoter in the brain of schizophrenic patients: a preliminary report. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B, 60-66. doi: 10.1002/ajmg.b.30140
2. Aberg, K. A., McClay, J. L., Nerella, S., Clark, S., Kumar, G., Chen, W., et al. (2014). Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry 71, 255-264. doi: 10.1001/jamapsychiatry.2013.3730
3. Alcántara, S., Ruiz, M., D'Arcangelo, G., Ezan, F., de Lecea, L., Curran, T., et al. (1998). Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse. J. Neurosci. 18, 7779-7799.
4. + neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors.Psychopharmacology (Berl) 204, 511-521. doi: 10.1007/s00213-009-1483-x
5. Beffert, U., Durudas, A., Weeber, E. J., Stolt, P. C., Giehl, K. M., Sweatt, J. D., et al. (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, 2041-2052. doi: 10.1523/jneurosci.4566-05.2006
6. Benes, F. M., Lim, B., Matzilevich, D., Walsh, J. P., Subburaju, S., and Minns, M. (2007). Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc. Natl. Acad. Sci. U S A 104, 10164-10169. doi: 10.1073/pnas.0703806104
7. Blaze, J., Scheuing, L., and Roth, T. L. (2013). Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy. Dev. Neurosci. 35, 306-316. doi: 10.1159/000350716
8. Bock, H. H., Jossin, Y., May, P., Bergner, O., and Herz, J. (2004). Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled-1. J. Biol. Chem. 279, 33471-33479. doi: 10.1074/jbc.m401770200
9. Brigman, J. L., Padukiewicz, K. E., Sutherland, M. L., and Rothblat, L. A. (2006). Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav. Neurosci. 120, 984-988. doi: 10.1037/0735-7044.120.4.984
10. Caruncho, H. J., Dopeso-Reyes, I. G., Loza, M. I., and Rodríguez, M. A. (2004). A GABA, reelin and the neurodevelopmental hypothesis of schizophrenia. Crit. Rev. Neurobiol. 16, 25-32. doi: 10.1615/CritRevNeurobiol.v16.i12.20
11. Chen, Y., Kundakovic, M., Agis-Balboa, R. C., Pinna, G., and Grayson, D. R. (2007). Induction of the reelin promoter by retinoic acid is mediated by Sp1. J. Neurochem.103, 650-665. doi: 10.1111/j.1471-4159.2007.04797.x
12. 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. doi: 10.1093/nar/gkf401
13. Cohen, S. M., Nichols, A., Wyatt, R., and Pollin, W. (1974). The administration of methionine to chronic schizophrenic patients: a review of ten studies. Biol. Psychiatry8, 209-225.
14. Costa, E., Chen, Y., Davis, J., Dong, E., Noh, J. S., Tremolizzo, L., et al. (2003). REELIN and schizophrenia: a disease at the interface of the genome and the epigenome. Mol. Interv. 2, 47-57. doi: 10.1124/mi.2.1.47
15. 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 vulnerability. Neurobiol. Dis. 8, 723-742. doi: 10.1006/nbdi.2001.0436
16. D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., and Curran, T. (1999). Reelin is a ligand for lipoprotein receptors. Neuron 24, 471-479. doi: 10.1016/S0896-6273(00)80860-0
17. D'Arcangelo, G., Miao, G. G., Chen, S. C., Soares, H. D., Morgan, J. I., and Curran, T. (1995). A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719-723. doi: 10.1038/374719a0
18. Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., and Binelli, S. (2015). Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.Am. J. Hum. Genet. 96, 992-1000. doi: 10.1016/j.ajhg.2015.04.020
19. 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. U S A 102, 12578-12583. doi: 10.1073/pnas.0505394102
20. Dong, E., Caruncho, H., Liu, W. S., Smalheiser, N. R., Grayson, D. R., Costa, E., et al. (2003). A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes. Proc. Natl. Acad. Sci. U S A 100, 5479-5484. doi: 10.1073/pnas.1031602100
21. Dong, E., Guidotti, A., Grayson, D. R., and Costa, E. (2007). Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters.Proc. Natl. Acad. Sci. U S A 104, 4676-4681. doi: 10.1073/pnas.0700529104
22. Dong, E., Tueting, P., Matrisciano, F., Grayson, D. R., and Guidotti, A. (2016). Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs.Transl. Psychiatry 6:e711. doi: 10.1038/tp.2015.191
23. Fatemi, S. H. (2002). The role of Reelin in pathology of autism. Mol. Psychiatry 7, 919-920. doi: 10.1038/sj.mp.4001248
24. Fatemi, S. H., Earle, J. A., and McMenomy, T. (2000). Hippocampal CA4 Reelin-positive neurons. Mol. Psychiatry 5:571. doi: 10.1038/sj.mp.4000794
25. Fenton, E. Y., Fournier, N. M., Lussier, A. L., Romay-Tallon, R., Caruncho, H. J., and Kalynchuk, L. E. (2015). Imipramine protects against the deleterious effects of chronic corticosterone on depression-like behavior, hippocampal reelin expression and neuronal maturation. Prog. Neuropsychopharmacol. Biol. Psychiatry 60, 52-59. doi: 10.1016/j.pnpbp.2015.02.001
26. Folsom, T. D., and Fatemi, S. H. (2013). The involvement of Reelin in neurodevelopmental disorders. Neuropharmacology 68, 122-135. doi: 10.1016/j.neuropharm.2012.08.015
27. Glantz, L. A., and Lewis, D. A. (2001). Dendritic spine density in schizophrenia and depression. Arch. Gen. Psychiatry 58:203. doi: 10.1001/archpsyc.58.2.203
28. Goldowitz, D., and Koch, J. (1986). Performance of normal and neurological mutant mice on radial arm maze and active avoidance tasks. Behav. Neural Biol. 46, 216-226. doi: 10.1016/s0163-1047(86)90696-5
29. Grayson, D. R., Chen, Y., Costa, E., Dong, E., Guidotti, A., Kundakovic, M., et al. (2006). The human reelin gene: transcription factors (+), repressors (-) and the methylation switch (+/-) in schizophrenia. Pharmacol. Ther. 111, 272-286. doi: 10.1016/j.pharmthera.2005.01.007
30. Grayson, D. R., Chen, Y., Dong, E., Kundakovic, M., and Guidotti, A. (2009). From trans-methylation to cytosine methylation: evolution of the methylation hypothesis of schizophrenia. Epigenetics 4, 144-149. doi: 10.4161/epi.4.3.8534
31. Grayson, D. R., and Guidotti, A. (2013). The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 38, 138-166. doi: 10.1038/npp.2012.125
32. Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., et al. (2005). Reelin promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. U S A 102, 9341-9346. doi: 10.1073/pnas.0503736102
33. Guidotti, A., Auta, J., Davis, J. M., Di-Giorgi-Gerevni, V., Dwivedi, Y., Grayson, D. R., et al. (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch. Gen. Psychiatry 57, 1061-1069. doi: 10.1001/archpsyc.57.11.1061
34. Guidotti, A., Ruzicka, W., Grayson, D. R., Veldic, M., Pinna, G., Davis, J. M., et al. (2007). S-adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psychosis. Neuroreport 18, 57-60. doi: 10.1097/wnr.0b013e32800fefd7
35. Hadj-Sahraoui, N., Frédéric, F., Delhaye-Bouchaud, N., and Mariani, J. (1996). Gender effect on Purkinje cell loss in the cerebellum of the heterozygous reeler mouse. J. Neurogenet. 11, 45-58. doi: 10.3109/01677069609107062
36. Herz, J., and Chen, Y. (2006). Reelin, lipoprotein receptors and synaptic plasticity.Nat. Rev. Neurosci. 7, 850-859. doi: 10.1038/nrn2009
37. Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., et al. (1999). Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.Neuron 24, 481-489. doi: 10.1016/s0896-6273(00)80861-2
38. Hong, S. E., Shugart, Y. Y., Huang, D. T., Shahwan, S. A., Grant, P. E., Hourihane, J. O., et al. (2000). Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human Reelin mutations. Nat. Genet. 26, 93-96. doi: 10.1038/79246
39. Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., and Martin, N. D. (1993). A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema. Neuropediatrics 24, 43-46. doi: 10.1055/s-2008-1071511
40. Howell, K. R., and Pillai, A. (2015). Long-term effects of prenatal hypoxia on schizophrenia-like phenotype in heterozygous reeler mice. Mol. Neurobiol. doi: 10.1007/s12035-015-9265-4 [Epub ahead of print].
41. Huang, H. S., Matevossian, A., Whittle, C., Kim, S. Y., Schumacher, A., Baker, S. P., et al. (2007). Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J. Neurosci. 27, 11254-11262. doi: 10.1523/JNEUROSCI.3272-07.2007
42. Iafrati, J., Orejarena, M. J., Lassalle, O., Bouamrane, L., Gonzalez-Campo, C., and Chavis, P. (2014). Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway. Mol. Psychiatry 19, 417-426. doi: 10.1038/mp.2013.66
43. Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., et al. (1998). A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl. Acad. Sci. U S A 95, 15718-15723. doi: 10.1073/pnas.95.26.15718
44. Jossin, Y., Bar, I., Ignatova, N., Tissir, F., De Rouvroit, C. L., and Goffinet, A. M. (2003). The reelin signaling pathway: some recent developments. Cereb. Cortex 13, 627-633. doi: 10.1093/cercor/13.6.627
45. Kadriu, B., Guidotti, A., Chen, Y., and Grayson, D. R. (2012). DNA methyltransferases1 (DNMT1) and 3a (DNMT3a) colocalize with GAD67-positive neurons in the GAD67-GFP mouse brain. J. Comp. Neurol. 520, 1951-1964. doi: 10.1002/cne.23020
46. Kobow, K., Jeske, I., Hildebrandt, M., Hauke, J., Hahnen, E., Buslei, R., et al. (2009). Increased Reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J. Neuropathol. Exp. Neurol. 68, 356-364. doi: 10.1097/NEN.0b013e31819ba737
47. Krueger, D. D., Howell, J. L., Hebert, B. F., Olausson, P., Taylor, J. R., and Nairn, A. C. (2006). Assessment of cognitive function in the heterozygous reeler mouse.Psychopharmacology (Berl) 189, 95-104. doi: 10.1007/s00213-006-0530-0
48. Kundakovic, M., Chen, Y., Costa, E., and Grayson, D. R. (2007). DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol. Pharmacol. 71, 644-653. doi: 10.1124/mol.106.030635
49. Kundakovic, M., Chen, Y., Guidotti, A., and Grayson, D. R. (2009). The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol. Pharmacol. 75, 342-354. doi: 10.1124/mol.108.051763
50. Kuo, G., Arnaud, L., Kronstad-O'Brien, P., and Cooper, J. A. (2005). Absence of Fyn and Src causes a reeler-like phenotype. J. Neurosci. 25, 8578-8586. doi: 10.1523/JNEUROSCI.1656-05.2005
51. Lacor, P. N., Grayson, D. R., Auta, J., Sugaya, I., Costa, E., and Guidotti, A. (2000). Reelin secretion from glutamatergic neurons in culture is independent from neurotransmitter regulation. Proc. Natl. Acad. Sci. U S A 97, 3556-3561. doi: 10.1073/pnas.97.7.3556
52. Levenson, J. M., Qiu, S., and Weeber, E. J. (2008). The role of reelin in adult synaptic function and the genetic and epigenetic regulation of the reelin gene. Biochim. Biophys. Acta 1779, 422-431. doi: 10.1016/j.bbagrm.2008.01.001
53. Levenson, J. M., Roth, T. L., Lubin, F. D., Miller, C. A., Huang, I. C., Desai, P., et al. (2006). Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem. 281, 15763-15773. doi: 10.1074/jbc.m511767200
54. Lintas, C., and Persico, A. M. (2010). Neocortical Reelin promoter methylation increases significantly after puberty. Neuroreport 21, 114-118. doi: 10.1097/WNR.0b013e328334b343
55. Liu, W. S., Pesold, C., Rodriguez, M. A., Carboni, G., Auta, J., Lacor, P., et al. (2001). Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc. Natl. Acad. Sci. U S A98, 3477-3482. doi: 10.1073/pnas.051614698
56. Lussier, A. L., Caruncho, H. J., and Kalynchuk, L. E. (2009). Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus. Neurosci. Lett. 460, 170-174. doi: 10.1016/j.neulet.2009.05.050
57. Lussier, A. L., Lebedeva, K., Fenton, E. Y., Guskjolen, A., Caruncho, H. J., and Kalynchuk, L. L. E. (2013). The progressive development of depression-like behavior in corticosterone-treated rats is paralleled by slowed granule cell maturation and decreased reelin expression in the adult dentate gyrus. Neuropharmacology 71, 174-183. doi: 10.1016/j.neuropharm.2013.04.012
58. Lussier, A. L., Romay-Tallón, R., Kalynchuk, L. E., and Caruncho, H. J. (2011). Reelin as a putative vulnerability factor for depression: examining the depressogenic effects of repeated corticosterone in heterozygous reeler mice. Neuropharmacology 60, 1064-1074. doi: 10.1016/j.neuropharm.2010.09.007
59. Maloku, E., Covelo, I. R., Hanbauer, I., Guidotti, A., Kadriu, B., Hu, Q., et al. (2010). Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression. Proc. Natl. Acad. Sci. U S A 107, 4407-4411. doi: 10.1073/pnas.0914483107
60. Marrone, M. C., Marinelli, S., Biamonte, F., Keller, F., Sgobio, C. A., Ammassari-Teule, M., et al. (2006). Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Eur. J. Neurosci. 24, 2061-2070. doi: 10.1111/j.1460-9568.2006.05083.x
61. Matrisciano, F., Dong, E., Gavin, D. P., Nicoletti, F., and Guidotti, A. (2011). Activation of group II metabotropic glutamate receptors promotes DNA demethylation in the mouse brain. Mol. Pharmacol. 80, 174-182. doi: 10.1124/mol.110.070896
62. Matrisciano, F., Tueting, P., Dalal, I., Kadriu, B., Grayson, D. R., Davis, J. M., et al. (2013). Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.Neuropharmacology 68, 184-194. doi: 10.1016/j.neuropharm.2012.04.013
63. Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., and Bouchard, L. (2008). Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am. J. Hum. Genet. 82, 696-711. doi: 10.1016/j.ajhg.2008.01.008
64. Mitchell, C. P., Chen, Y., Kundakovic, M., Costa, E., and Grayson, D. R. (2005). Histone deacetylase inhibitors decrease reelin promoter methylation in vitro. J. Neurochem. 93, 483-492. doi: 10.1111/j.1471-4159.2005.03040.x
65. Niu, S., Renfro, A., Quattrocchi, C. C., Sheldon, M., and D'Arcangelo, G. (2004). Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway. Neuron 41, 71-84. doi: 10.1016/s0896-6273(03)00819-5
66. Niu, S., Yabut, O., and D'Arcangelo, G. (2008). The Reelin signaling pathway promotes dendritic spine development in hippocampal neurons. J. Neurosci. 28, 10339-10348. doi: 10.1523/JNEUROSCI.1917-08.2008
67. Noh, J. S., Sharma, R. P., Veldic, M., Salvacion, A. A., Jia, X., Chen, Y., et al. (2005). DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc. Natl. Acad. Sci. U S A 102, 1749-1754. doi: 10.1073/pnas.0409648102
68. Ognibene, E., Adriani, W., Macrì, S., and Laviola, G. (2007). Neurobehavioural disorders in the infant reeler mouse model: interaction of genetic vulnerability and consequences of maternal separation. Behav. Brain Res. 177, 142-149. doi: 10.1016/j.bbr.2006.10.027
69. Palacios-Garcia, I., Lara-Vásquez, A., Montiel, J. F., Díaz-Véliz, G. F., Sepúlveda, H., Utreras, E., et al. (2015). Prenatal stress down-regulates reelin expression by methylation of its promoter and induces adult behavioral impairments in rats. PLoS One 10:e0117680. doi: 10.1371/journal.pone.0117680
70. Pesold, C., Impagnatiello, F., Pisu, M. G., Uzunov, D. P., Costa, E., Guidotti, A., et al. (1998). Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc. Natl. Acad. Sci. U S A 95, 3221-3226. doi: 10.1073/pnas.95.6.3221
71. 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. U S A 96, 3217-3222. doi: 10.1073/pnas.96.6.3217
72. Ptak, C., and Petronis, A. (2010). Epigenetic approaches to psychiatric disorders.Dialogues Clin. Neurosci. 12, 25-35.
73. Pujadas, L., Gruart, A., Bosch, C., Delgado, L., Teixeira, C. M., Rossi, D., et al. (2010). Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J. Neurosci. 30, 4636-4649. doi: 10.1523/JNEUROSCI.5284-09.2010
74. Qin, L., Tu, W., Sun, W., Zhang, J., Chen, Y., and Zhao, H. (2011). Retardation of neurobehavioral development and reelin down-regulation regulated by further DNA methylation in the hippocampus of the rat pups are associated with maternal deprivation. Behav. Brain Res. 217, 142-147. doi: 10.1016/j.bbr.2010.10.018
75. Razin, A., and Shemer, R. (1995). DNA methylation in early development. Hum. Mol. Genet. 4, 1751-1755.
76. Rice, D. S., Sheldon, M., D'Arcangelo, G., Nakajima, K., Goldowitz, D., and Curran, T. (1998). Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125, 3719-3729.
77. Rodriguez, M. A., Pesold, C., Liu, W. S., Kriho, V., Guidotti, A., Pappas, G. D., et al. (2000). Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex. Proc. Natl. Acad. Sci. U S A 97, 3550-3555. doi: 10.1073/pnas.97.7.3550
78. Rogers, J. T., Rusiana, I., Trotter, J., Zhao, L., Donaldson, E., Pak, D. T., et al. (2011). Reelin supplementation enhances cognitive ability, synaptic plasticity and dendritic spine density. Learn. Mem. 18, 558-564. doi: 10.1101/lm.2153511
79. Rogers, J. T., Zhao, L., Trotter, J. H., Rusiana, I., Peters, M. M., Li, Q., et al. (2013). Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. J. Psychopharmacol.27, 386-395. doi: 10.1177/0269881112463468
80. 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, 385-397. doi: 10.1038/sj.mp.4001954
81. Satta, R., Maloku, E., Zhubi, A., Pibiri, F., Hajos, M., Costa, E., et al. (2008). Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. Proc. Natl. Acad. Sci. U S A 105, 16356-16361. doi: 10.1073/pnas.0808699105
82. Sharma, R. P., Grayson, D. R., and Gavin, D. P. (2008). Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection. Schizophr. Res. 98, 111-117. doi: 10.1016/j.schres.2007.09.020
83. Shifman, S., Johannesson, M., Bronstein, M., Chen, S. X., Collier, D. A., Craddock, N. J., et al. (2008). Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 4:e28. doi: 10.1371/journal.pgen.0040028
84. Stranahan, A. M., Salas-Vega, S., Jiam, N. T., and Gallagher, M. (2011). Interference with reelin signaling in the lateral entorhinal cortex impairs spatial memory.Neurobiol. Learn. Mem. 96, 150-155. doi: 10.1016/j.nlm.2011.03.009
85. Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H. H., Hiesberger, T., et al. (2004). Receptor clustering is involved in Reelin signaling. Mol. Cell Biol. 24, 1378-1386. doi: 10.1128/mcb.24.3.1378-1386.2004
86. Sui, L., and Li, B.-M. (2010). Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rt hippocampus: role of DNA methylation and histone acetylation. Steroids 75, 988-997. doi: 10.1016/j.steroids.2010.06.005
87. Sui, L., Wang, Y., Ju, L.-H., and Chen, M. (2012). Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long term potentiation in rat medial prefrontal cortex. Neurobiol. Learn. Mem. 97, 425-440. doi: 10.1016/j.nlm.2012.03.007
88. Szyf, M. (2009). Epigenetics, DNA methylation and chromatin modifying drugs. Annu. Rev. Pharmacol. Toxicol. 49, 243-263. doi: 10.1146/annurev-pharmtox-061008-103102
89. Tochigi, M., Iwamoto, K., Bundo, M., Komori, A., Sasaki, T., Kato, N., et al. (2008). Methylation status of the reelin promoter region in the brain of schizophrenia subjects. Biol. Psychiatry 63, 530-533. doi: 10.1016/j.biopsych.2007.07.003
90. Tremolizzo, L., Carboni, G., Ruzicka, W. B., Mitchell, C. P., Sugaya, I., Tueting, P., et al. (2002). An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl. Acad. Sci. U S A 99, 17095-17100. doi: 10.1073/pnas.262658999
91. Tremolizzo, L., Doueiri, M. S., Dong, E., Grayson, D. R., Davis, J., Pinna, G., et al. (2005). Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol. Psychiatry 57, 500-509. doi: 10.1016/j.biopsych.2004.11.046
92. Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., et al. (1999). Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689-701. doi: 10.1016/s0092-8674(00)80782-5
93. Tueting, P., Costa, E., Dwivedi, Y., Guidotti, A., Impagnatiello, F., Manev, R., et al. (1999). The phenotypic characteristics of heterozygous reeler mouse. Neuroreport10, 1329-1334. doi: 10.1097/00001756-199904260-00032
94. Tueting, P., Davis, J. M., Veldic, M., Pibiri, F., Kadriu, B., Guidotti, A., et al. (2010). L-methionine decreases dendritic spine density in mouse frontal cortex. Neuroreport 21, 543-548. doi: 10.1097/WNR.0b013e3283373126
95. Tueting, P., Doueiri, M. S., Guidotti, A., Davis, J. M., and Costa, E. (2006). Reelin down-regulation in mice and psychosis endophenotypes. Neurosci. Biobehav. Rev.30, 1065-1077. doi: 10.1016/j.neubiorev.2006.04.001
96. Veldic, M., Caruncho, H. J., Liu, W. S., Davis, J., Satta, R., Grayson, D. R., et al. (2004). DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc. Natl. Acad. Sci. U S A 101, 348-353. doi: 10.1073/pnas.2637013100
97. Veldic, M., Kadriu, B., Maloku, E., Agis-Balboa, R. C., Guidotti, A., Davis, J. M., et al. (2007). Costa E. Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophr. Res. 91, 51-61. doi: 10.1016/j.schres.2006.11.029
98. Ventruti, A., Kazdoba, T. M., Niu, S., and D'Arcangelo, G. (2011). Reelin deficiency causes specific defects in the molecular composition of the synapses in the adult brain.Neuroscience 189, 32-42. doi: 10.1016/j.neuroscience.2011.05.050
99. Wang, Z., Hong, Y., Zou, L., Zhong, R., Zhu, B., Shen, N., et al. (2014). Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B, 192-200. doi: 10.1002/ajmg.b.32222
100. Weaver, I. C., Champagne, F. A., Brown, S. E., Dymov, S., Sharma, S., Meaney, M. J., et al. (2005). Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci.25, 11045-11054. doi: 10.1523/JNEUROSCI.3652-05.2005
101. Weaver, I. C., Meaney, M. J., and Szyf, M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc. Natl. Acad. Sci. U S A 103, 3480-3485. doi: 10.1073/pnas.0507526103
102. Wedenoja, J., Tuulio-Henriksson, A., Suvisaari, J., Loukola, A., Paunio, T., Partonen, T., et al. (2010). Replication of association between working memory and Reelin, a potential modifier gene in schizophrenia. Biol. Psychiatry 67, 983-991. doi: 10.1016/j.biopsych.2009.09.026
103. Wyatt, R. J., Benedict, A., and Davis, J. (1971). Biochemical and sleep studies of schizophrenia: a review of the literature-1960-1970. Schiz. Bull. 4, 10-44. doi: 10.1093/schbul/1.4.10
104. Zhang, H., Liu, X., Zhang, C., Mundo, E., Macciardi, F., Grayson, D. R., et al. (2002). Reelin gene alleles and susceptibility to autism spectrum disorders. Mol. Psychiatry 7, 1012-1017. doi: 10.1038/sj.mp.4001124
105. Zhubi, A., Chen, Y., Dong, E., Cook, E. H., Guidotti, A., and Grayson, D. R. (2014). Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Transl. Psychiatry 4:e349. doi: 10.1038/tp.2013.123