Skip to main content

Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects

Molecular Neurobiology volume 58, pages 777–794 (2021)Cite this article

Abstract

Background

Stress increases DNA methylation, primarily a suppressive epigenetic mechanism catalyzed by DNA methyltransferases (DNMT), and decreases the expression of genes involved in neuronal plasticity and mood regulation. Despite chronic antidepressant treatment decreases stress-induced DNA methylation, it is not known whether inhibition of DNMT would convey rapid antidepressant-like effects.

Aim

This work tested such a hypothesis and evaluated whether a behavioral effect induced by DNMT inhibitors (DNMTi) corresponds with changes in DNA methylation and transcript levels in genes consistently associated with the neurobiology of depression and synaptic plasticity (BDNF, TrkB, 5-HT1A, NMDA, and AMPA).

Methods

Male Wistar rats received intraperitoneal (i.p.) injection of two pharmacologically different DNMTi (5-AzaD 0.2 and 0.6 mg/kg or RG108 0.6 mg/kg) or vehicle (1 ml/kg), 1 h or 7 days before the learned helplessness test (LH). DNA methylation in target genes and the correspondent transcript levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC) using meDIP-qPCR. In parallel separate groups, the antidepressant-like effect of 5-AzaD and RG108 was investigated in the forced swimming test (FST). The involvement of cortical BDNF-TrkB-mTOR pathways was assessed by intra-ventral medial PFC (vmPFC) injections of rapamycin (mTOR inhibitor), K252a (TrkB receptor antagonist), or vehicle (0.2 μl/side).

Results

We found that both 5-AzaD and RG108 acutely and 7 days before the test decreased escape failures in the LH. LH stress increased DNA methylation and decreased transcript levels of BDNF IV and TrkB in the PFC, effects that were not significantly attenuated by RG108 treatment. The systemic administration of 5-AzaD (0.2 mg/kg) and RG108 (0.2 mg/kg) induced an antidepressant-like effect in FST, which was, however, attenuated by TrkB and mTOR inhibition into the vmPFC.

Conclusion

These findings suggest that acute inhibition of stress-induced DNA methylation promotes rapid and sustained antidepressant effects associated with increased BDNF-TrkB-mTOR signaling in the PFC.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Vigo D, Thornicroft G, Atun R (2016) Estimating the true global burden of mental illness. Lancet Psychiatry 3(2):171–178. https://doi.org/10.1016/S2215-0366(15)00505-2

    Article  PubMed  Google Scholar 

  2. Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33(1):88–109. https://doi.org/10.1038/sj.npp.1301574

    CAS  Article  PubMed  Google Scholar 

  3. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, Fifth Edn. Arlington, VA

  4. Shadrina M, Bondarenko EA, Slominsky PA (2018) Genetics factors in major depression disease. Front Psychiatry 9:334. https://doi.org/10.3389/fpsyt.2018.00334

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yang T, Nie Z, Shu H, Kuang Y, Chen X, Cheng J, Yu S, Liu H (2020) The role of BDNF on neural plasticity in depression. Front Cell Neurosci 14:82. https://doi.org/10.3389/fncel.2020.00082

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT (2009) Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. J Psychiatr Res 43(14):1175–1184. https://doi.org/10.1016/j.jpsychires.2009.03.008

    CAS  Article  PubMed  Google Scholar 

  7. Emon MPZ, Das R, Nishuty NL, Shalahuddin Qusar MMA, Bhuiyan MA, Islam MR (2020) Reduced serum BDNF levels are associated with the increased risk for developing MDD: a case-control study with or without antidepressant therapy. BMC Res Notes 13(1):83. https://doi.org/10.1186/s13104-020-04952-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Guilloux JP, Douillard-Guilloux G, Kota R, Wang X, Gardier AM, Martinowich K, Tseng GC, Lewis DA et al (2012) Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry 17(11):1130–1142. https://doi.org/10.1038/mp.2011.113

    CAS  Article  PubMed  Google Scholar 

  9. Thompson Ray M, Weickert CS, Wyatt E, Webster MJ (2011) Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci 36(3):195–203. https://doi.org/10.1503/jpn.100048

    Article  PubMed  Google Scholar 

  10. Tripp A, Oh H, Guilloux JP, Martinowich K, Lewis DA, Sibille E (2012) Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry 169(11):1194–1202. https://doi.org/10.1176/appi.ajp.2012.12020248

    Article  PubMed  PubMed Central  Google Scholar 

  11. Duman RS (2002) Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry 17(Suppl 3):306–310. https://doi.org/10.1016/s0924-9338(02)00654-5

    Article  PubMed  Google Scholar 

  12. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127. https://doi.org/10.1016/j.biopsych.2006.02.013

    CAS  Article  PubMed  Google Scholar 

  13. Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15(3 Pt 1):1768–1777

    CAS  Article  Google Scholar 

  14. Taliaz D, Stall N, Dar DE, Zangen A (2010) Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 15(1):80–92. https://doi.org/10.1038/mp.2009.67

    CAS  Article  PubMed  Google Scholar 

  15. Koshimizu H, Kiyosue K, Hara T, Hazama S, Suzuki S, Uegaki K, Nagappan G, Zaitsev E et al (2009) Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival. Mol Brain 2:27. https://doi.org/10.1186/1756-6606-2-27

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077. https://doi.org/10.1038/nn1510

    CAS  Article  PubMed  Google Scholar 

  17. Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64(6):527–532. https://doi.org/10.1016/j.biopsych.2008.05.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54(1):70–75. https://doi.org/10.1016/s0006-3223(03)00181-1

    CAS  Article  PubMed  Google Scholar 

  19. Koponen E, Lakso M, Castren E (2004) Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. Brain Res Mol Brain Res 130(1–2):81–94. https://doi.org/10.1016/j.molbrainres.2004.07.010

    CAS  Article  PubMed  Google Scholar 

  20. Rantamaki T, Hendolin P, Kankaanpaa A, Mijatovic J, Piepponen P, Domenici E, Chao MV, Mannisto PT et al (2007) Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32(10):2152–2162. https://doi.org/10.1038/sj.npp.1301345

    CAS  Article  PubMed  Google Scholar 

  21. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A et al (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23(1):349–357

    CAS  Article  Google Scholar 

  22. Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22(8):3251–3261 20026292

    CAS  Article  Google Scholar 

  23. Ye Y, Wang G, Wang H, Wang X (2011) Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neurosci Lett 503(1):15–19. https://doi.org/10.1016/j.neulet.2011.07.055

    CAS  Article  PubMed  Google Scholar 

  24. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54(7):703–709. https://doi.org/10.1016/s0006-3223(03)00073-8

    CAS  Article  PubMed  Google Scholar 

  25. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258. https://doi.org/10.1124/pr.111.005108

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Molteni R, Calabrese F, Cattaneo A, Mancini M, Gennarelli M, Racagni G, Riva MA (2009) Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine. Neuropsychopharmacology 34(6):1523–1532. https://doi.org/10.1038/npp.2008.208

    CAS  Article  PubMed  Google Scholar 

  27. Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16(7):2365–2372

    CAS  Article  Google Scholar 

  28. Russo-Neustadt A, Beard RC, Cotman CW (1999) Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 21(5):679–682. https://doi.org/10.1016/S0893-133X(99)00059-7

    CAS  Article  PubMed  Google Scholar 

  29. Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ (2004) Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 29(12):2189–2199. https://doi.org/10.1038/sj.npp.1300514

    CAS  Article  PubMed  Google Scholar 

  30. Castren E, Rantamaki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70(5):289–297. https://doi.org/10.1002/dneu.20758

    CAS  Article  PubMed  Google Scholar 

  31. Castren E, Rantamaki T (2010) Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment. CNS Drugs 24(1):1–7. https://doi.org/10.2165/11530010-000000000-00000

    CAS  Article  PubMed  Google Scholar 

  32. Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM (1996) BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res 710(1–2):11–20. https://doi.org/10.1016/0006-8993(95)01289-3

    CAS  Article  PubMed  Google Scholar 

  33. Wong YH, Lee CM, Xie W, Cui B, Poo MM (2015) Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin. Proc Natl Acad Sci U S A 112(32):E4475–E4484. https://doi.org/10.1073/pnas.1511830112

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Sakata K, Martinowich K, Woo NH, Schloesser RJ, Jimenez DV, Ji Y, Shen L, Lu B (2013) Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance. Proc Natl Acad Sci U S A 110(37):15103–15108. https://doi.org/10.1073/pnas.1222872110

    Article  PubMed  PubMed Central  Google Scholar 

  35. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F (1993) Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150(11):1731–1733. https://doi.org/10.1176/ajp.150.11.1731

    CAS  Article  PubMed  Google Scholar 

  36. Deutschenbaur L, Beck J, Kiyhankhadiv A, Muhlhauser M, Borgwardt S, Walter M, Hasler G, Sollberger D et al (2016) Role of calcium, glutamate and NMDA in major depression and therapeutic application. Prog Neuro-Psychopharmacol Biol Psychiatry 64:325–333. https://doi.org/10.1016/j.pnpbp.2015.02.015

    CAS  Article  Google Scholar 

  37. Frye MA, Tsai GE, Huggins T, Coyle JT, Post RM (2007) Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol Psychiatry 61(2):162–166. https://doi.org/10.1016/j.biopsych.2006.01.024

    CAS  Article  PubMed  Google Scholar 

  38. Ghasemi M, Phillips C, Trillo L, De Miguel Z, Das D, Salehi A (2014) The role of NMDA receptors in the pathophysiology and treatment of mood disorders. Neurosci Biobehav Rev 47:336–358. https://doi.org/10.1016/j.neubiorev.2014.08.017

    CAS  Article  PubMed  Google Scholar 

  39. Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62(11):1310–1316. https://doi.org/10.1016/j.biopsych.2007.03.017

    CAS  Article  PubMed  Google Scholar 

  40. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982) Increased serum glutamate in depressed patients. Archiv Psychiat Nervenkrankheiten 232(4):299–304. https://doi.org/10.1007/BF00345492

    CAS  Article  Google Scholar 

  41. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW (2000) Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 47(7):586–593. https://doi.org/10.1016/s0006-3223(99)00284-x

    CAS  Article  PubMed  Google Scholar 

  42. Mathews DC, Henter ID, Zarate CA (2012) Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 72(10):1313–1333. https://doi.org/10.2165/11633130-000000000-00000

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G (1998) Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37(3):124–129. https://doi.org/10.1159/000026491

    CAS  Article  PubMed  Google Scholar 

  44. Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR Jr, Kawahara R (2006) Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 30(6):1155–1158. https://doi.org/10.1016/j.pnpbp.2006.03.036

    CAS  Article  Google Scholar 

  45. Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG (2014) A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord 156:24–35. https://doi.org/10.1016/j.jad.2013.11.014

    CAS  Article  PubMed  Google Scholar 

  46. Bartanusz V, Aubry JM, Pagliusi S, Jezova D, Baffi J, Kiss JZ (1995) Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience 66(2):247–252. https://doi.org/10.1016/0306-4522(95)00084-v

    CAS  Article  PubMed  Google Scholar 

  47. Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J Neurosci 16(1):274–282

    CAS  Article  Google Scholar 

  48. Marsden WN (2011) Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression. Med Hypotheses 77(4):508–528. https://doi.org/10.1016/j.mehy.2011.06.021

    CAS  Article  PubMed  Google Scholar 

  49. Masrour FF, Peeri M, Azarbayjani MA, Hosseini MJ (2018) Voluntary exercise during adolescence mitigated negative the effects of maternal separation stress on the depressive-like behaviors of adult male rats: role of NMDA receptors. Neurochem Res 43(5):1067–1074. https://doi.org/10.1007/s11064-018-2519-6

    CAS  Article  PubMed  Google Scholar 

  50. McCarthy DJ, Alexander R, Smith MA, Pathak S, Kanes S, Lee CM, Sanacora G (2012) Glutamate-based depression GBD. Med Hypotheses 78(5):675–681. https://doi.org/10.1016/j.mehy.2012.02.009

    CAS  Article  PubMed  Google Scholar 

  51. Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60(5):1650–1657. https://doi.org/10.1111/j.1471-4159.1993.tb13387.x

    CAS  Article  PubMed  Google Scholar 

  52. Sathyanesan M, Haiar JM, Watt MJ, Newton SS (2017) Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice. Stress 20(2):197–204. https://doi.org/10.1080/10253890.2017.1298587

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Weiland NG, Orchinik M, Tanapat P (1997) Chronic corticosterone treatment induces parallel changes in N-methyl-D-aspartate receptor subunit messenger RNA levels and antagonist binding sites in the hippocampus. Neuroscience 78(3):653–662. https://doi.org/10.1016/s0306-4522(96)00619-7

    CAS  Article  PubMed  Google Scholar 

  54. Jaso BA, Niciu MJ, Iadarola ND, Lally N, Richards EM, Park M, Ballard ED, Nugent AC et al (2017) Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol 15(1):57–70. https://doi.org/10.2174/1570159x14666160321123221

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354. https://doi.org/10.1016/s0006-3223(99)00230-9

    CAS  Article  PubMed  Google Scholar 

  56. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185(1):1–10. https://doi.org/10.1016/0014-2999(90)90204-j

    CAS  Article  PubMed  Google Scholar 

  57. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. https://doi.org/10.1001/archpsyc.63.8.856

    CAS  Article  PubMed  Google Scholar 

  58. Krystal JH, Sanacora G, Duman RS (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73(12):1133–1141. https://doi.org/10.1016/j.biopsych.2013.03.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Du J, Suzuki K, Wei Y, Wang Y, Blumenthal R, Chen Z, Falke C, Zarate CA Jr et al (2007) The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32(4):793–802. https://doi.org/10.1038/sj.npp.1301178

    CAS  Article  PubMed  Google Scholar 

  60. Freudenberg F, Celikel T, Reif A (2015) The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity? Neurosci Biobehav Rev 52:193–206. https://doi.org/10.1016/j.neubiorev.2015.03.005

    CAS  Article  PubMed  Google Scholar 

  61. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ (2012) Ketamine for depression: where do we go from here? Biol Psychiatry 72(7):537–547. https://doi.org/10.1016/j.biopsych.2012.05.003

    CAS  Article  Google Scholar 

  62. Ionescu DF, Swee MB, Pavone KJ, Taylor N, Akeju O, Baer L, Nyer M, Cassano P et al (2016) Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine: secondary analysis of an open-label study. J Clin Psychiatry 77(6):e719–e725. https://doi.org/10.4088/JCP.15m10056

    Article  PubMed  Google Scholar 

  63. Price RB, Mathew SJ (2015) Does ketamine have anti-suicidal properties? Current status and future directions. CNS Drugs 29(3):181–188. https://doi.org/10.1007/s40263-015-0232-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Koike H, Fukumoto K, Iijima M, Chaki S (2013) Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. Behav Brain Res 238:48–52. https://doi.org/10.1016/j.bbr.2012.10.023

    CAS  Article  PubMed  Google Scholar 

  65. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964. https://doi.org/10.1126/science.1190287

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK (2012) Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71(11):996–1005. https://doi.org/10.1016/j.biopsych.2011.09.030

    CAS  Article  PubMed  Google Scholar 

  67. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475(7354):91–95. https://doi.org/10.1038/nature10130

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63(4):349–352. https://doi.org/10.1016/j.biopsych.2007.05.028

    CAS  Article  PubMed  Google Scholar 

  69. Hashimoto K (2011) Role of the mTOR signaling pathway in the rapid antidepressant action of ketamine. Expert Rev Neurother 11(1):33–36. https://doi.org/10.1586/ern.10.176

    CAS  Article  PubMed  Google Scholar 

  70. Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224(1):107–111. https://doi.org/10.1016/j.bbr.2011.05.035

    CAS  Article  PubMed  Google Scholar 

  71. Luscher B, Feng M, Jefferson SJ (2020) Antidepressant mechanisms of ketamine: focus on GABAergic inhibition. Adv Pharmacol 89:43–78. https://doi.org/10.1016/bs.apha.2020.03.002

    Article  PubMed  Google Scholar 

  72. Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007) Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32(9):1888–1902. https://doi.org/10.1038/sj.npp.1301312

    CAS  Article  PubMed  Google Scholar 

  73. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, Jurjus GJ, Dieter L et al (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16(1):69–82. https://doi.org/10.1017/S1461145712000016

    CAS  Article  PubMed  Google Scholar 

  74. Toth E, Gersner R, Wilf-Yarkoni A, Raizel H, Dar DE, Richter-Levin G, Levit O, Zangen A (2008) Age-dependent effects of chronic stress on brain plasticity and depressive behavior. J Neurochem 107(2):522–532. https://doi.org/10.1111/j.1471-4159.2008.05642.x

    CAS  Article  PubMed  Google Scholar 

  75. Ferrari F, Villa RF (2017) The neurobiology of depression: an integrated overview from biological theories to clinical evidence. Mol Neurobiol 54(7):4847–4865. https://doi.org/10.1007/s12035-016-0032-y

    CAS  Article  PubMed  Google Scholar 

  76. Kaufman J, DeLorenzo C, Choudhury S, Parsey RV (2016) The 5-HT1A receptor in major depressive disorder. Eur Neuropsychopharmacol 26(3):397–410. https://doi.org/10.1016/j.euroneuro.2015.12.039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Yohn CN, Gergues MM, Samuels BA (2017) The role of 5-HT receptors in depression. Mol Brain 10(1):28. https://doi.org/10.1186/s13041-017-0306-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Cheetham SC, Crompton MR, Katona CL, Horton RW (1990) Brain 5-HT1 binding sites in depressed suicides. Psychopharmacology 102(4):544–548. https://doi.org/10.1007/bf02247138

    CAS  Article  PubMed  Google Scholar 

  79. Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G (1998) Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 18(18):7394–7401

    CAS  Article  Google Scholar 

  80. Carr GV, Lucki I (2011) The role of serotonin receptor subtypes in treating depression: a review of animal studies. Psychopharmacology 213(2–3):265–287. https://doi.org/10.1007/s00213-010-2097-z

    CAS  Article  PubMed  Google Scholar 

  81. Joca SR, Padovan CM, Guimaraes FS (2003) Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus prevents learned helplessness development. Brain Res 978(1–2):177–184. https://doi.org/10.1016/s0006-8993(03)02943-3

    CAS  Article  PubMed  Google Scholar 

  82. Pitchot W, Hansenne M, Pinto E, Reggers J, Fuchs S, Ansseau M (2005) 5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior. Biol Psychiatry 58(11):854–858. https://doi.org/10.1016/j.biopsych.2005.05.042

    CAS  Article  PubMed  Google Scholar 

  83. Savitz JB, Drevets WC (2013) Neuroreceptor imaging in depression. Neurobiol Dis 52:49–65. https://doi.org/10.1016/j.nbd.2012.06.001

    CAS  Article  PubMed  Google Scholar 

  84. Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54(7):597–606

    CAS  Article  Google Scholar 

  85. Depoortere R, Papp M, Gruca P, Lason-Tyburkiewicz M, Niemczyk M, Varney MA, Newman-Tancredi A (2019) Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model. J Psychopharmacol 33(11):1456–1466. https://doi.org/10.1177/0269881119860666

    CAS  Article  PubMed  Google Scholar 

  86. Newman-Tancredi A, Bardin L, Auclair A, Colpaert F, Depoortere R, Varney MA (2018) NLX-112, a highly selective 5-HT1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT1A receptors, respectively. Brain Res 1688:1–7. https://doi.org/10.1016/j.brainres.2018.03.016

    CAS  Article  PubMed  Google Scholar 

  87. Ago Y, Tanabe W, Higuchi M, Tsukada S, Tanaka T, Yamaguchi T, Igarashi H, Yokoyama R et al (2019) (R)-ketamine induces a greater increase in prefrontal 5-HT release than (S)-ketamine and ketamine metabolites via an AMPA receptor-independent mechanism. Int J Neuropsychopharmacol 22(10):665–674. https://doi.org/10.1093/ijnp/pyz041

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Pham TH, Mendez-David I, Defaix C, Guiard BP, Tritschler L, David DJ, Gardier AM (2017) Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice. Neuropharmacology 112(Pt A):198–209. https://doi.org/10.1016/j.neuropharm.2016.05.010

    CAS  Article  PubMed  Google Scholar 

  89. Jin HJ, Pei L, Li YN, Zheng H, Yang S, Wan Y, Mao L, Xia YP et al (2017) Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression. Sci Rep 7(1):14926. https://doi.org/10.1038/s41598-017-13929-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Takeuchi N, Nonen S, Kato M, Wakeno M, Takekita Y, Kinoshita T, Kugawa F (2017) Therapeutic response to paroxetine in major depressive disorder predicted by DNA methylation. Neuropsychobiology 75(2):81–88. https://doi.org/10.1159/000480512

    CAS  Article  PubMed  Google Scholar 

  91. Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003) Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60(8):804–815. https://doi.org/10.1001/archpsyc.60.8.804

    CAS  Article  PubMed  Google Scholar 

  92. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8(5):355–367. https://doi.org/10.1038/nrn2132

    CAS  Article  PubMed  Google Scholar 

  93. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455(7215):894–902. https://doi.org/10.1038/nature07455

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Zhu K, Ou Yang TH, Dorie V, Zheng T, Anastassiou D (2019) Meta-analysis of expression and methylation signatures indicates a stress-related epigenetic mechanism in multiple neuropsychiatric disorders. Transl Psychiatry 9(1):32. https://doi.org/10.1038/s41398-018-0358-5

    Article  PubMed  PubMed Central  Google Scholar 

  95. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293(5532):1068–1070. https://doi.org/10.1126/science.1063852

    CAS  Article  PubMed  Google Scholar 

  96. Tognini P, Napoli D, Pizzorusso T (2015) Dynamic DNA methylation in the brain: a new epigenetic mark for experience-dependent plasticity. Front Cell Neurosci 9:331. https://doi.org/10.3389/fncel.2015.00331

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Wang P, Lv Q, Mao Y, Zhang C, Bao C, Sun H, Chen H, Yi Z et al (2018) HTR1A/1B DNA methylation may predict escitalopram treatment response in depressed Chinese Han patients. J Affect Disord 228:222–228. https://doi.org/10.1016/j.jad.2017.12.010

    CAS  Article  PubMed  Google Scholar 

  98. Le Francois B, Soo J, Millar AM, Daigle M, Le Guisquet AM, Leman S, Minier F, Belzung C et al (2015) Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site. Neurobiol Dis 82:332–341. https://doi.org/10.1016/j.nbd.2015.07.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. Gassen NC, Fries GR, Zannas AS, Hartmann J, Zschocke J, Hafner K, Carrillo-Roa T, Steinbacher J et al (2015) Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Sci Signal 8(404):ra119. https://doi.org/10.1126/scisignal.aac7695

    CAS  Article  PubMed  Google Scholar 

  100. Higuchi F, Uchida S, Yamagata H, Otsuki K, Hobara T, Abe N, Shibata T, Watanabe Y (2011) State-dependent changes in the expression of DNA methyltransferases in mood disorder patients. J Psychiatr Res 45(10):1295–1300. https://doi.org/10.1016/j.jpsychires.2011.04.008

    Article  PubMed  Google Scholar 

  101. Sales AJ, Biojone C, Terceti MS, Guimaraes FS, Gomes MV, Joca SR (2011) Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors. Br J Pharmacol 164(6):1711–1721. https://doi.org/10.1111/j.1476-5381.2011.01489.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Sales AJ, Joca SR (2016) Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels. Acta Neuropsychiatrica 28(1):11–22. https://doi.org/10.1017/neu.2015.40

    Article  PubMed  Google Scholar 

  103. Sales AJ, Joca SRL (2018) Antidepressant administration modulates stress-induced DNA methylation and DNA methyltransferase expression in rat prefrontal cortex and hippocampus. Behav Brain Res 343:8–15. https://doi.org/10.1016/j.bbr.2018.01.022

    CAS  Article  PubMed  Google Scholar 

  104. LaPlant Q, Vialou V, Covington HE 3rd, Dumitriu D, Feng J, Warren BL, Maze I, Dietz DM et al (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 13(9):1137–1143. https://doi.org/10.1038/nn.2619

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Xing B, Liu P, Xu WJ, Xu FY, Dang YH (2014) Effect of microinjecting of 5-aza-2-deoxycytidine into ventrolateral orbital cortex on depressive-like behavior in rats. Neurosci Lett 574:11–14. https://doi.org/10.1016/j.neulet.2014.04.050

    CAS  Article  PubMed  Google Scholar 

  106. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302(5646):890–893. https://doi.org/10.1126/science.1090842

    CAS  Article  PubMed  Google Scholar 

  107. Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N, Inoue T, Kusumi I et al (2011) DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS One 6(8):e23881. https://doi.org/10.1371/journal.pone.0023881

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9(4):519–525. https://doi.org/10.1038/nn1659

    CAS  Article  PubMed  Google Scholar 

  109. Kang HJ, Kim JM, Lee JY, Kim SY, Bae KY, Kim SW, Shin IS, Kim HR et al (2013) BDNF promoter methylation and suicidal behavior in depressive patients. J Affect Disord 151(2):679–685. https://doi.org/10.1016/j.jad.2013.08.001

    CAS  Article  PubMed  Google Scholar 

  110. Chan RF, Turecki G, Shabalin AA, Guintivano J, Zhao M, Xie LY, van Grootheest G, Kaminsky ZA et al (2020) Cell type-specific methylome-wide association studies implicate neurotrophin and innate immune signaling in major depressive disorder. Biol Psychiatry 87(5):431–442. https://doi.org/10.1016/j.biopsych.2019.10.014

    CAS  Article  PubMed  Google Scholar 

  111. Chang LC, Jamain S, Lin CW, Rujescu D, Tseng GC, Sibille E (2014) A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies. PLoS One 9(3):e90980. https://doi.org/10.1371/journal.pone.0090980

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. Keller S, Sarchiapone M, Zarrilli F, Tomaiuolo R, Carli V, Angrisano T, Videtic A, Amato F et al (2011) TrkB gene expression and DNA methylation state in Wernicke area does not associate with suicidal behavior. J Affect Disord 135(1–3):400–404. https://doi.org/10.1016/j.jad.2011.07.003

    CAS  Article  PubMed  Google Scholar 

  113. Wang P, Zhang C, Lv Q, Bao C, Sun H, Ma G, Fang Y, Yi Z et al (2018) Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients. Eur J Clin Pharmacol 74(8):1011–1020. https://doi.org/10.1007/s00228-018-2463-z

    CAS  Article  PubMed  Google Scholar 

  114. Aberg KA, Dean B, Shabalin AA, Chan RF, Han LKM, Zhao M, van Grootheest G, Xie LY et al (2018) Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0247-6

  115. Boersma GJ, Lee RS, Cordner ZA, Ewald ER, Purcell RH, Moghadam AA, Tamashiro KL (2014) Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats. Epigenetics 9(3):437–447. https://doi.org/10.4161/epi.27558

    Article  PubMed  Google Scholar 

  116. Chandrasekar R (2013) Alcohol and NMDA receptor: current research and future direction. Front Mol Neurosci 6:14. https://doi.org/10.3389/fnmol.2013.00014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Kaut O, Schmitt I, Hofmann A, Hoffmann P, Schlaepfer TE, Wullner U, Hurlemann R (2015) Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression. Eur Arch Psychiatry Clin Neurosci 265(4):331–341. https://doi.org/10.1007/s00406-014-0572-y

    Article  PubMed  Google Scholar 

  118. Jobe EM, Zhao X (2017) DNA methylation and adult neurogenesis. Brain Plast 3(1):5–26. https://doi.org/10.3233/BPL-160034

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sweatt JD (2016) Dynamic DNA methylation controls glutamate receptor trafficking and synaptic scaling. J Neurochem 137(3):312–330. https://doi.org/10.1111/jnc.13564

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Mahar I, Bambico FR, Mechawar N, Nobrega JN (2014) Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev 38:173–192. https://doi.org/10.1016/j.neubiorev.2013.11.009

    CAS  Article  PubMed  Google Scholar 

  121. Fukumoto K, Iijima M, Funakoshi T, Chaki S (2018) Role of 5-HT1A receptor stimulation in the medial prefrontal cortex in the sustained antidepressant effects of ketamine. Int J Neuropsychopharmacol 21(4):371–381. https://doi.org/10.1093/ijnp/pyx116

    CAS  Article  PubMed  Google Scholar 

  122. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ (2014) Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 29(7):419–423. https://doi.org/10.1016/j.eurpsy.2013.10.005

    CAS  Article  PubMed  Google Scholar 

  123. Sales A, Biojone C, Joca S (2016) Site-specific delivery of epigenetic modulating drugs into the rat brain. In: Karpova N (ed) Epigenetic methods in neuroscience research, Neuromethods, vol 105. Humana press, New York

    Chapter  Google Scholar 

  124. Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates, 7th edn. Academic Press, Cambridge

  125. Abel EL, Bilitzke PJ (1990) A possible alarm substance in the forced swimming test. Physiol Behav 48(2):233–239

    CAS  Article  Google Scholar 

  126. Bonefeld BE, Elfving B, Wegener G (2008) Reference genes for normalization: a study of rat brain tissue. Synapse 62(4):302–309. https://doi.org/10.1002/syn.20496

    CAS  Article  PubMed  Google Scholar 

  127. Karpova NN, Umemori J (2016) Protocol for methylated DNA immunoprecipitation (meDIP) analysis. In: Epigenetic methods in neuroscience research, vol 105. Humana Press, New York, pp. 97–114

    Chapter  Google Scholar 

  128. Roy B, Shelton RC, Dwivedi Y (2017) DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. J Psychiatr Res 89:115–124. https://doi.org/10.1016/j.jpsychires.2017.02.005

    Article  PubMed  PubMed Central  Google Scholar 

  129. Casarotto PC, de Bortoli VC, Correa FM, Resstel LB, Zangrossi H Jr (2010) Panicolytic-like effect of BDNF in the rat dorsal periaqueductal grey matter: the role of 5-HT and GABA. Int J Neuropsychopharmacol 13(5):573–582. https://doi.org/10.1017/S146114570999112X

    CAS  Article  PubMed  Google Scholar 

  130. Fernandez Macedo GV, Cladouchos ML, Sifonios L, Cassanelli PM, Wikinski S (2013) Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm. Psychopharmacology 225(3):647–659. https://doi.org/10.1007/s00213-012-2859-x

    CAS  Article  PubMed  Google Scholar 

  131. Yan HC, Cao X, Das M, Zhu XH, Gao TM (2010) Behavioral animal models of depression. Neurosci Bull 26(4):327–337. https://doi.org/10.1007/s12264-010-0323-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. Urb M, Anier K, Matsalu T, Aonurm-Helm A, Tasa G, Koppel I, Zharkovsky A, Timmusk T et al (2019) Glucocorticoid receptor stimulation resulting from early life stress affects expression of DNA methyltransferases in rat prefrontal cortex. J Mol Neurosci 68(1):99–110. https://doi.org/10.1007/s12031-019-01286-z

    CAS  Article  PubMed  Google Scholar 

  133. Morris MJ, Adachi M, Na ES, Monteggia LM (2014) Selective role for DNMT3a in learning and memory. Neurobiol Learn Mem 115:30–37. https://doi.org/10.1016/j.nlm.2014.06.005

    CAS  Article  PubMed  Google Scholar 

  134. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13(4):423–430. https://doi.org/10.1038/nn.2514

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, Sweatt JD (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281(23):15763–15773. https://doi.org/10.1074/jbc.M511767200

    CAS  Article  PubMed  Google Scholar 

  136. Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z, Szyf M, Anisman H (2008) GABAA receptor promoter hypermethylation in suicide brain: Implications for the involvement of epigenetic processes. Biol Psychiatry 64(8):645–652. https://doi.org/10.1016/j.biopsych.2008.05.028

    CAS  Article  PubMed  Google Scholar 

  137. Hsieh MT, Lin CC, Lee CT, Huang TL (2019) Abnormal brain-derived neurotrophic factor exon IX promoter methylation, protein, and mRNA levels in patients with major depressive disorder. J Clin Med 8(5). https://doi.org/10.3390/jcm8050568

  138. Efstathopoulos P, Andersson F, Melas PA, Yang LL, Villaescusa JC, Ruegg J, Ekstrom TJ, Forsell Y et al (2018) NR3C1 hypermethylation in depressed and bullied adolescents. Transl Psychiatry 8(1):121. https://doi.org/10.1038/s41398-018-0169-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Haghighi F, Xin Y, Chanrion B, O’Donnell AH, Ge Y, Dwork AJ, Arango V, Mann JJ (2014) Increased DNA methylation in the suicide brain. Dialogues Clin Neurosci 16(3):430–438

    Article  Google Scholar 

  140. Morris MJ, Na ES, Autry AE, Monteggia LM (2016) Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice. Neurobiol Learn Mem 135:139–145. https://doi.org/10.1016/j.nlm.2016.08.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. Elliott E, Manashirov S, Zwang R, Gil S, Tsoory M, Shemesh Y, Chen A (2016) Dnmt3a in the medial prefrontal cortex regulates anxiety-like behavior in adult mice. J Neurosci 36(3):730–740. https://doi.org/10.1523/JNEUROSCI.0971-15.2016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Momparler RL (2005) Pharmacology of 5-Aza-2′-deoxycytidine (decitabine). Semin Hematol 42(3 Suppl 2):S9–S16

    CAS  Article  Google Scholar 

  143. Fandy TE (2009) Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases. Curr Med Chem 16(17):2075–2085. https://doi.org/10.2174/092986709788612738

    CAS  Article  PubMed  Google Scholar 

  144. Brueckner B, Garcia Boy R, Siedlecki P, Musch T, Kliem HC, Zielenkiewicz P, Suhai S, Wiessler M et al (2005) Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 65(14):6305–6311. https://doi.org/10.1158/0008-5472.CAN-04-2957

    CAS  Article  PubMed  Google Scholar 

  145. Schirrmacher E, Beck C, Brueckner B, Schmitges F, Siedlecki P, Bartenstein P, Lyko F, Schirrmacher R (2006) Synthesis and in vitro evaluation of biotinylated RG108: a high affinity compound for studying binding interactions with human DNA methyltransferases. Bioconjug Chem 17(2):261–266. https://doi.org/10.1021/bc050300b

    CAS  Article  PubMed  Google Scholar 

  146. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632. https://doi.org/10.1038/tp.2015.136

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. Schneeberger Y, Stenzig J, Hubner F, Schaefer A, Reichenspurner H, Eschenhagen T (2016) Pharmacokinetics of the experimental non-nucleosidic DNA methyl transferase inhibitor N-phthalyl-L-tryptophan (RG 108) in rats. Basic Clin Pharmacol Toxicol 118(5):327–332. https://doi.org/10.1111/bcpt.12514

    CAS  Article  PubMed  Google Scholar 

  148. Marcucci G, Silverman L, Eller M, Lintz L, Beach CL (2005) Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 45(5):597–602. https://doi.org/10.1177/0091270004271947

    CAS  Article  PubMed  Google Scholar 

  149. Champagne FA, Francis DD, Mar A, Meaney MJ (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav 79(3):359–371

    CAS  Article  Google Scholar 

  150. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G et al (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69(8):754–761. https://doi.org/10.1016/j.biopsych.2010.12.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Ardalan M, Rafati AH, Nyengaard JR, Wegener G (2017) Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. Br J Pharmacol 174(6):483–492. https://doi.org/10.1111/bph.13714

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Ardalan M, Wegener G, Rafati AH, Nyengaard JR (2017) S-ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression. Int J Neuropsychopharmacol 20(3):247–256. https://doi.org/10.1093/ijnp/pyw098

    CAS  Article  PubMed  Google Scholar 

  153. Ardalan M, Elfving B, Rafati AH, Mansouri M, Zarate CA Jr, Mathe AA, Wegener G (2020) Rapid effects of S-ketamine on the morphology of hippocampal astrocytes and BDNF serum levels in a sex-dependent manner. Eur Neuropsychopharmacol 32:94–103. https://doi.org/10.1016/j.euroneuro.2020.01.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18(1). https://doi.org/10.1093/ijnp/pyu033

  155. Lener MS, Kadriu B, Zarate CA Jr (2017) Ketamine and beyond: investigations into the potential of glutamatergic agents to treat depression. Drugs 77(4):381–401. https://doi.org/10.1007/s40265-017-0702-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. Hashimoto K (2011) The role of glutamate on the action of antidepressants. Prog Neuro-Psychopharmacol Biol Psychiatry 35(7):1558–1568. https://doi.org/10.1016/j.pnpbp.2010.06.013

    CAS  Article  Google Scholar 

  157. Castren E (2005) Is mood chemistry? Nat Rev Neurosci 6(3):241–246. https://doi.org/10.1038/nrn1629

    CAS  Article  PubMed  Google Scholar 

  158. Courtney MJ, Akerman KE, Coffey ET (1997) Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J Neurosci 17(11):4201–4211

    CAS  Article  Google Scholar 

  159. Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136(1–2):29–37. https://doi.org/10.1016/j.molbrainres.2004.12.020

    CAS  Article  PubMed  Google Scholar 

  160. Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65(9):760–769. https://doi.org/10.1016/j.biopsych.2008.11.028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Han M, Hashimoto K (2015) Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology 232(23):4325–4335. https://doi.org/10.1007/s00213-015-4062-3

    CAS  Article  PubMed  Google Scholar 

  162. Shirayama Y, Hashimoto K (2018) Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol 21(1):84–88. https://doi.org/10.1093/ijnp/pyx108

    CAS  Article  PubMed  Google Scholar 

  163. Maussion G, Yang J, Suderman M, Diallo A, Nagy C, Arnovitz M, Mechawar N, Turecki G (2014) Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide. Epigenetics 9(8):1061–1070. https://doi.org/10.4161/epi.29068

    Article  PubMed  PubMed Central  Google Scholar 

  164. Mifsud KR, Saunderson EA, Spiers H, Carter SD, Trollope AF, Mill J, Reul JM (2017) Rapid down-regulation of glucocorticoid receptor gene expression in the dentate gyrus after acute stress in vivo: role of DNA methylation and microRNA activity. Neuroendocrinology 104(2):157–169. https://doi.org/10.1159/000445875

    CAS  Article  PubMed  Google Scholar 

  165. Martin-Hernandez D, Tendilla-Beltran H, Madrigal JLM, Garcia-Bueno B, Leza JC, Caso JR (2019) Chronic mild stress alters kynurenine pathways changing the glutamate neurotransmission in frontal cortex of rats. Mol Neurobiol 56(1):490–501. https://doi.org/10.1007/s12035-018-1096-7

    CAS  Article  PubMed  Google Scholar 

  166. van Eijk KR, de Jong S, Boks MP, Langeveld T, Colas F, Veldink JH, de Kovel CG, Janson E et al (2012) Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects. BMC Genomics 13:636. https://doi.org/10.1186/1471-2164-13-636

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. Lea AJ, Vockley CM, Johnston RA, Del Carpio CA, Barreiro LB, Reddy TE, Tung J (2018) Genome-wide quantification of the effects of DNA methylation on human gene regulation. eLife 7. https://doi.org/10.7554/eLife.37513

Download references

Acknowledgments

The authors acknowledge Prof. Francisco Silveira Guimarães for his helpful contribution to the statistical analysis and Flávia Fiacadori Salata for her technical assistance. We are thankful to Prof. Gregers Wegener for his comments and suggestions on the manuscript.

Funding

This work was supported by research grants from the Research Foundation of the State of São Paulo (FAPESP, grant numbers: S.R.L.J., 2011/17281-7; 2012/17626-7; A.J.S., 2015/01955-0), CNPQ (304780/2018-9; 06648/2014-8).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Amanda J. Sales & Izaque S. Maciel

  2. FMRP-USP, Av Bandeirantes, 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Amanda J. Sales

  3. Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Angélica C. D. R. Suavinha & Sâmia R. L. Joca

  4. Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Sâmia R. L. Joca

  5. FCFRP-USP, Av Café, sn, Monte Alegre, Ribeirão Preto, SP, 14040-903, Brazil

    Sâmia R. L. Joca

Authors
  1. Amanda J. Sales
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Izaque S. Maciel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angélica C. D. R. Suavinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sâmia R. L. Joca
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.J.S. performed experiments, analyzed data, and wrote the paper. I.S.M. and AC.D.R.S. performed experiments. S.R.L.J. designed the experiments, supervised the project, and contributed with writing the paper. All authors discussed the results, implications, and commented on the manuscript at all stages.

Corresponding authors

Correspondence to Amanda J. Sales or Sâmia R. L. Joca.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

• DNMT inhibitors (5-AzaD and RG108) induce antidepressant-like properties in rats

• Acute DNA methylation inhibition promotes rapid and sustained effects in rats

• DNMT inhibitors increase BDNF-TrkB-mTOR signaling in the rat prefrontal cortex

Electronic Supplementary Material

Supplementary Table 1
figure 7

Padded amplicon sequences of Taqman gene expression predesigned assays used. (PNG 143 kb)

Full size image
Supplementary Table 2
figure 8

Abbreviations: DNMTi – DNA methyltransferase inhibitors, LH – learned helplessness, ANOVA – analysis of variance. Statistical significance at p < 0.05. (PNG 27 kb)

Full size image
Supplementary Table 3
figure 9

Abbreviations: ANOVA – analysis of variance. Statistical significance at p < 0.05 (PNG 52 kb)

Full size image
Supplementary Table 4
figure 10

Abbreviations: ANOVA – analysis of variance. Statistical significance at p < 0.05. (PNG 15 kb)

Full size image
Supplementary Table 5
figure 11

Abbreviations: DNMTi – DNA methyltransferase inhibitors, FST – forced swimming test, OFT – open field test, PT – pretest, T – test, ANOVA – analysis of variance. Statistical significance at p < 0.05. (PNG 34 kb)

Full size image

High resolution Image (EPS 3304 kb)

High resolution Image (EPS 353 kb)

High resolution Image (EPS 395 kb)

High resolution Image (EPS 111 kb)

High resolution Image (EPS 220 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sales, A.J., Maciel, I.S., Suavinha, A.C.D.R. et al. Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects. Mol Neurobiol 58, 777–794 (2021). https://doi.org/10.1007/s12035-020-02145-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-020-02145-4

Keywords

  • DNA methylation
  • DNMT
  • Antidepressant
  • RG108
  • 5-AzaD
  • RNAm