Advertisement

The ERK Pathway: Molecular Mechanisms and Treatment of Depression

  • John Q. WangEmail author
  • Limin Mao
Article
  • 50 Downloads

Abstract

Major depressive disorder is a chronic debilitating mental illness. Its pathophysiology at cellular and molecular levels is incompletely understood. Increasing evidence supports a pivotal role of the mitogen-activated protein kinase (MAPK), in particular the extracellular signal-regulated kinase (ERK) subclass of MAPKs, in the pathogenesis, symptomatology, and treatment of depression. In humans and various chronic animal models of depression, the ERK signaling was significantly downregulated in the prefrontal cortex and hippocampus, two core areas implicated in depression. Inhibiting the ERK pathway in these areas caused depression-like behavior. A variety of antidepressants produced their behavioral effects in part via normalizing the downregulated ERK activity. In addition to ERK, the brain-derived neurotrophic factor (BDNF), an immediate upstream regulator of ERK, the cAMP response element-binding protein (CREB), a transcription factor downstream to ERK, and the MAPK phosphatase (MKP) are equally vulnerable to depression. While BDNF and CREB were reduced in their activity in the prefrontal cortex and hippocampus of depressed animals, MKP activity was enhanced in parallel. Chronic antidepressant treatment readily reversed these neurochemical changes. Thus, ERK signaling in the depression-implicated brain regions was disrupted during the development of depression, which contributes to the long-lasting and transcription-dependent neuroadaptations critical for enduring depression-like behavior and the therapeutic effect of antidepressants.

Keywords

Depression Antidepressant ERK MAPK phosphatase BDNF CREB Frontal cortex Hippocampus 

Notes

Funding Information

This work was supported by NIH grants R01DA10355 (JQW) and R01MH61469 (JQW).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Volmat V, Pouyssegur J (2001) Spatiotemporal regulation of the p42/p44 MAPK pathway. Biol Cell 93:71–79PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Mao LM, Wang JQ (2016) Synaptically localized mitogen-activated protein kinases: local substrates and regulation. Mol Neurobiol 53:6309–6315PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Silverstein AM, Barrow CA, Davis AJ, Mumby MC (2002) Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc Natl Acad Sci U S A 99:4221–4226PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY (2002) The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem 277:31818–31825PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Mao L, Yang L, Arora A, Choe ES, Zhang G, Liu Z, Fibuch EE, Wang JQ (2005) Role of protein phosphatase 2A in mGluR5-regulated MEK/ERK phosphorylation in neurons. J Biol Chem 280:12602–12610PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wang JQ, Fibuch EE, Mao L (2007) Regulation of mitogen-activated protein kinases by glutamate receptors. J Neurochem 100:1–11PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN (2001) Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem 77:916–928PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Liu W, Ge T, Leng Y, Pan Z, Fan J, Yang W, Cui R (2017) The role of neural plasticity in depression: From hippocampus to prefrontal cortex. Neural Plast 2017:6871089PubMedPubMedCentralGoogle Scholar
  11. 11.
    Dwivedi Y, Rizavi HS, Conley RR, Pandey GN (2006) ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Mol Psychiatry 11:86–98PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Dwivedi Y, Rizavi HS, Zhang H, Roberts RC, Conley RR, Pandey GN (2009) Aberrant extracellular signal-regulated kinase (ERK)1/2 signalling in suicide brain: role of ERK kinase 1 (MEK1). Int J Neuropsychopharmacol 12:1337–1354PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Sheehan TP, Neve RL, Duman RS, Russell DS (2003) Antidepressant effect of the calcium-activated tyrosine kinase Pyk2 in the lateral septum. Biol Psychiatry 54:540–551PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Meller E, Shen C, Nikolao TA, Jensen C, Tsimberg Y, Chen J, Gruen RJ (2003) Region-specific effects of acute and repeated restraint stress on the phosphorylation of mitogen-activated protein kinases. Brain Res 979:57–64PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Galeotti N, Ghelardini C (2012) Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol 15:781–793PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Schultz H, Sheehan TP, Duman RS, Russell DS (2001) Regulation of ERK activity in brain by chronic stress and antidepressants. Soc Neurosci Abstr 906:p6Google Scholar
  17. 17.
    Qi X, Lin W, Li J, Pan Y, Wang W (2006) The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress. Behav Brain Res 175:233–240PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Qi X, Lin W, Li J, Li H, Wang W, Wang D, Sun M (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Feng P, Guan Z, Yang X, Fang J (2003) Impairments of ERK signal transduction in the brain in a rat model of depression induced neonatal exposure of clomipramine. Brain Res 991:195–205PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR (2008) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 63:353–359PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A (2011) The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression. J Mol Neurosci 45:246–255PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Xiong Z, Jiang B, Wu PF, Tian J, Shi LL, Gu J, Hu ZL, Fu H et al (2011) Antidepressant effects of a plant-derived flavonoid baicalein involving extracellular signal-regulated kinases cascade. Biol Pharm Bull 34:253–259PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Jia W, Liu R, Shi J, Wu B, Dang W, Du Y, Zhou Q, Wang J et al (2013) Differential regulation of MAPK phosphorylation in the dorsal hippocampus in response to prolonged morphine withdrawal-induced depressive-like symptoms in mice. PLoS One 8:e66111PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Leem YH, Yoon SS, Kim YH, Jo SA (2014) Disrupted MEK/ERK signaling in the medial orbital cortex and dorsal endopiriform nuclei of the prefrontal cortex in a chronic restraint stress mouse model of depression. Neurosci Lett 580:163–168PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, Pang Q (2014) Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res 271:116–121PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Luo YW, Xu Y, Cao WY, Zhong XL, Duan J, Wang XQ, Hu ZL, Li F et al (2015) Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. Neuropharmacology 89:318–324PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Shibata S, Linuma M, Soumiya H, Fukumitsu H, Furukawa Y, Furukawa S (2015) A novel 2-decenoic acid thioester ameliorates corticosterone-induced depression- and anxiety-like behaviors and normalizes reduced hippocampal signal transduction in treated mice. Pharmacol Res Perspect 3:e00132PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Wang M, Zhou W, Zhou X, Zhuang F, Chen Q, Li M, Ma T, Gu S (2015) Antidepressant-like effects of alarin produced by activation of TrkB receptor signaling pathways in chronic stress mice. Behav Brain Res 280:128–140PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Wang X, Xie Y, Zhang T, Bo S, Bai X, Liu H, Li T, Liu S et al (2016) Resveratrol reverses chronic restraint stress-induced depression-like behavior: involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats. Brain Res Bull 125:134–143PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Wang Q, Shao F, Wang W (2018) Region-dependent alterations in cognitive function and ERK1/2 signaling in the PFC in rats after social defeat stress. Neural Plast 2018:9870985PubMedPubMedCentralGoogle Scholar
  31. 31.
    Li E, Deng H, Wang B, Fu W, You Y, Tian S (2016) Apelin-13 exerts antidepressant-like and recognition memory improving activities in stressed rats. Eur Neuropsychopharmacol 26:420–430PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Li Y, Chen Y, Gao X, Zhang Z (2017) The behavioral deficits and cognitive impairment are correlated with decreased IGF-II and ERK in depressed mice induced by chronic unpredictable stress. Int J Neurosci 127:1096–1103PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Oh DR, Yoo JS, Kim Y, Kang H, Lee H, Lm SJ, Choi EJ, Jung MA et al (2018) Vaccinium bracteatum leaf extract reverses chronic restraint stress-induced depression-like behavior in mice: regulation of hypothalamic-pituitary-adrenal axis, serotonin turnover systems, and ERK/Akt phosphorylation. Front Pharmacol 9:604PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Takahashi K, Nakagawasai O, Nemoto W, Kadota S, Odaira T, Sakuma W, Arai Y, Tadano T et al (2018) Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice. Neuropharmacology 137:141–155PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Guan L, Jia N, Zhao X, Zhang X, Tang G, Yang L, Sun H, Wang D et al (2013) The involvement of ERK/CREB/Bcl-2 in depression-like behavior in prenatally stressed offspring rats. Brain Res Bull 99:1–8PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Budziszewska B, Szymanska M, Leskiewicz M, Basta-Kaim A, Jaworska-Feil L, Kubera M, Jantas D, Lason W (2010) The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphate level in the brain of prenatally stressed rats. J Physiol Pharmacol 61:207–215PubMedPubMedCentralGoogle Scholar
  37. 37.
    Kohler C, Chan-Palay V, Steinbusch H (1982) The distribution and origin of serotonin-containing fibers in the septal area: a combined immunohistochemical and fluorescent retrograde tracing study in the rat. J Comp Neurol 209:91–111PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Gall C, Moore RY (1984) Distribution of enkephalin, substance P, tyrosine hydroxylase, and 5-hydroxytryptamine immunoreactivity in the septal region of the rat. J Comp Neurol 225:212–227PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Kirby LG, Lucki I (1997) Interaction between the forced swimming test and fluoxetine treatment on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat. J Pharmacol Exp Ther 282:967–976PubMedPubMedCentralGoogle Scholar
  40. 40.
    Shen C, Li H, Meller E (2002) Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35S] GTPγS binding in rat brain regions. Neuropharmacology 42:1031–1038PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Watts SW (1998) Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor. Ann N Y Acad Sci 861:162–168PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Robertson ED, English JD, Adams JP, Selcher JC, Kondratick C, Sweatt JD (1999) The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 19:4337–4348CrossRefGoogle Scholar
  43. 43.
    Pandey GN, Dwivedi Y, Pandey SC, Conley RR, Roberts RC, Tamminga CA (1997) Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 228:111–114PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Reiach JS, Li PP, Warsh JJ, Kish SJ, Young LT (1999) Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims. J Affect Discord 56:141–151CrossRefGoogle Scholar
  45. 45.
    Dwivedi Y, Rizavi HS, Shukla PK, Lyons J, Faludi G, Palkovits M, Sarosi A, Conley RR et al (2004) Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits. Biol Psychiatry 55:234–243PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Shelton RC, Manier DH, Lewis DA (2009) Protein kinase A and C in postmortem prefrontal cortex from persons with major depression and normal controls. Int J Neuropsychopharmacol 12:1223–1232PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY (2016) The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. Neuroscience 322:358–369PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Fan J, Wei W, Liao X, Wang S (2017) Chronic social defeat stress leads to changes of behaviour and memory-associated proteins of young mice. Behav Brain Res 316:136–144CrossRefGoogle Scholar
  49. 49.
    Branski P, Palucha A, Szewczyk B, Wieronska JM, Pilc A, Nowak G (2008) Antidepressant-like activity of 8-Br-cAMP, a PKA activator, in the forced swim test. J Neural Transm (Vienna) 115:829–830CrossRefGoogle Scholar
  50. 50.
    Zeni AL, Zomkowski AD, Maraschin M, Rodrigues AL, Tasca CI (2012) Involvement of PKA, CaMKII, PKC, MAPK/ERK and PI3K in the acute antidepressant-like effect of ferulic acid in the tail suspension test. Pharmacol Biochem Behav 103:181–186PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Manosso LM, Moretti M, Ribeiro CM, Goncalves FM, Leal RB, Rodrigues ALS (2015) Antideppressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuro-Psychopharmacol Biol Psychiatry 59:59–67CrossRefGoogle Scholar
  52. 52.
    Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS (2010) A negative regulator o MAP kinase causes depressive behavior. Nat Med 16:1328–1332PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chen Y, Wang H, Zhang R, Wang H, Peng Z, Sun R, Tan Q (2012) Microinjection of sanguinarine into the ventrolateral orbital cortex inhibits Mkp-1 and exerts an antidepressant-like effect in rats. Neurosci Lett 506:327–331PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 23:7311–7316PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS (2007) A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 61:661–670PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Tronson NC, Schrick C, Fischer A, Sananbenesi F, Pages G, Pouyssegur J, Radulovic J (2008) Regulatory mechanisms of fear extinction and depression-like behavior. Neuropsychopharmacology 33:1570–1583PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Todorovic C, Sherrin T, Pitts M, Hippel C, Rayner M, Spiess J (2009) Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice. Neuropsychopharmacology 34:1416–1426PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Reus GZ, Vieira FG, Abelaira HM, Michels M, Tomaz DB, dos Santos MA, Carlessi AS, Neotti MV et al (2014) MAPK signaling correlates with the antidepressant effects of ketamine. J Psychiatr Res 55:15–21PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Qi X, Lin W, Wang D, Pan Y, Wang W, Sun M (2009) A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior. Behav Brain Res 199:203–209PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S (2003) An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4:964–968PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Satoh Y, Endo S, Nakata T, Kobayashi Y, Yamada K, Ikeda T, Takeuchi A, Hiramoto T et al (2011) ERK2 contributes to the control of social behaviors in mice. J Neurosci 31:11953–11967PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Fumagalli F, Molteni R, Calabrese F, Frasca A, Racagni G, Riva MA (2005) Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain. J Neurochem 93:1551–1560PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Chen YH, Zhang RG, Xue F, Wang HN, Chen YC, Hu GT, Peng Y, Peng ZW et al (2015) Quetiapine and repetitive transcranial magnetic stimulation ameliorate depression-like behaviors and up-regulate the proliferation of hippocampal-derived neural stem cells in a rat model of depression: the involvement of the BDNF/ERK signal pathway. Pharmacol Biochem Behav 136:39–46PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Islam MR, Moriquchi S, Tagashira H, Fukunaga K (2014) Revastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice. Neuroscience 272:116–230PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Liu D, Zhang Q, Gu J, Wang X, Xie K, Xian X, Wang J, Jiang H et al (2014) Resveratrol prevents impaired cognition induced by chronic unpredictable mild stress in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 49:21–29CrossRefGoogle Scholar
  66. 66.
    Yan T, Wu B, Liao ZZ, Liu B, Zhao X, Bi KS, Jia Y (2016) Brain-derived neurotrophic factor signaling mediates the antidepressant-like effect of the total flavonoids of Alpiniae oxyphyllae fructus in chronic unpredictable mild stress mice. Phytother Res 30:1493–1502PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Yang C, Ren Q, Qu Y, Zhang JC, Ma M, Dong C, Hashimoto K (2018) Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83:18–28PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Zhang L, Xu T, Wang S, Yu L, Liu D, Zhan R, Yu SY (2012) Curcumin produces antidepressant effects via activating MAPK/ERK-dependent brain-derived neurotrophic factor expression in the amygdala of mice. Behav Brain Res 235:67–72PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Li J, Luo Y, Zhang R, Shi H, Zhu W, Shi J (2015) Neuropeptide trefoil factor 3 reverses depressive-like behaviors by activation of BDNF-ERK-CREB signaling in olfactory bulbectomized rats. Int J Mol Sci 16:28386–28400PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Li CF, Chen XM, Chen SM, Mu RH, Liu BB, Luo L, Liu XL, Geng D et al (2016) Activation of hippocampal BDNF signaling is involved in the antidepressant-like effect of the NMDA receptor antagonist 7-chlorokynurenic acid. Brain Res 1630:73–82PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Domin H, Szewczyk B, Pochwat B, Wozniak M, Smialowska M (2017) Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence. Psychopharmacology 234:631–645PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Goncalves FM, Neis VB, Rieger DK, Lopes MW, Heinrich IA, Costa AP, Rodrigues ALS, Kaster MP et al (2017) Signaling pathways underlying the antidepressant-like effect of inosine in mice. Purinergic Signal 13:203–214PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Pochwat B, Rafalo-Ulinska A, Domin H, Misztak P, Nowak G, Szewczyk B (2017) Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonist (zinc and Ro 25-6981) in the forced swim test in rats. Neuropharmacology 125:333–342PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Sawamoto A, Okuyama S, Amakura Y, Yoshimura M, Yamada T, Yokogoshi H, Nakajima M, Furukawa Y (2017) 3,5,6,7,8,3′,4′,-Heptamethoxyflavone ameliorates depressive-like behavior and hippocampal neurochemical changes in chronic unpredictable mild stressed mice by regulating the brain-derived neurotrophic factor: requirement for ERK activation. Int J Mol Sci 18:E2133PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Wang JQ, Tang Q, Parelkar NK, Liu Z, Samdani S, Choe ES, Yang L, Mao L (2004) Glutamate signaling to Ras-MAPK in striatal neurons. Mol Neurobiol 29:1–14PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Xing J (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273:959–963PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Yamada S, Yamamoto H, Qzawa H, Riederer P, Saito T (2003) Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. J Neural Transm 110:671–680PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Laifenfeld D, Karry R, Grauer E, Klein E, Ben-Shachar D (2005) Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiol Dis 20:432–441PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Xu Y, Ku BS, Tie L, Yao HY, Jiang WG, Ma X, Li XJ (2006) Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res 1122:56–64PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Takahashi K, Nakagawasai O, Nemoto W, Odaira T, Arai Y, Hisamitsu T, Tan-No K (2017) Time-dependent role of prefrontal cortex and hippocampus on cognitive improvement by aripiprazole in olfactory bulbectomized mice. Eur Neuropsychopharmacol 27:1000–1010PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Dowlatshahi D, MacQueen GM, Wang JF, Young LT (1998) Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 352:1754–1755PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Thomas GM, Huganir RL (2004) MAPK cascade signaling and synaptic plasticity. Nat Rev Neurosci 5:173–183PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M (2004) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Yuan S, Jiang X, Zhou X, Zhang Y, Teng T, Xie P (2018) Inosine alleviates depression-like behavior and increases the activity of the ERK-CREB signaling in adolescent male rats. Neuroreport 29:1223–1229PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Iniquez SD, Cao JL, Kirk A et al (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12:200–209PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Schmidt HD, Banasr M, Duman RS (2008) Future antidepressant targets: neurotrophic factors and related signaling cascades. Drug Discov Today Ther Strateg 5:151–156PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    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 15:1768–1777PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Nibuya M, Takahashi M, Russell DS, Duman RS (1999) Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 267:81–84PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    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 60:804–815PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    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. Mol Brain Res 136:29–37PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A (2013) The effects of reboxetine treatment on depression-like behavior, brain neurotrophins, and ERK expression in rats exposed to chronic mild stress. J Mol Neurosci 50:88–97PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, Gordon E, Kemp AH et al (2009) Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 14:681–695PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Sheline Y, Wany P, Gado MH, Csemansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93:3908–3913PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bremner J, Narayan M, Anderson ER, Staib LH, Miller H, Charney DS (2000) Smaller hippocampal volume in major depression. Am J Psychiatry 157:115–117PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Ge JF, Gao WC, Cheng WM, Lu WL, Tang J, Peng L, Li N, Chen FH (2014) Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress. Eur Neuropsychopharmacol 24:172–180PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Sawamoto A, Okuyama S, Yamamoto K, Amakura Y, Yoshimura M, Nakajima M, Furukawa Y (2016) 3,5,6,7,8,3′,4′,-Heptamethoxyflavonel, a citrus flavonoid, ameliorates corticosterone-induced depression-like behavior and restores brain-derived neurotrophic factor expression, neurogenesis, and neuroplasticity in the hippocampus. Molecules 21:541PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ye M, Ke Y, Liu B, Yuan Y, Wang F, Bu S, Zhang Y (2017) Root bark of Morus alba ameliorates the depression-like behavior in diabetic rats. Neurosci Lett 637:136–141PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Wu R, Tao W, Zhang H, Xue W, Zou Z, Wu H, Cai B, Doron R et al (2016) Instant and persistent antidepressant response of gardenia yellow pigment is associated with acute protein synthesis and delayed upregulation of BDNF expression in the hippocampus. ACS Chem Neurosci 7:1068–1076PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Zhang Y, Ge JF, Wang FF, Liu F, Shi C, Li N (2017) Crassifoside H improve the depressive-like behavior of rats under chronic unpredictable mild stress: possible involved mechanisms. Brain Res Bull 135:77–84PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Zhao J, Luo D, Liang Z, Lao L, Rong J (2017) Plant natural product puerarin ameliorates depressive behaviors and chronic pain in mice with spared nerve injury (SNI). Mol Neurobiol 54:2801–2812PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Sawamoto A, Okuyama S, Amakura Y, Yamada R, Yoshimura M, Nakajima M, Furukawa Y (2018) Sansoninto as evidence-based remedial medicine for depression-like behavior. J Nat Med 72:118–126PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Schmidt HD, Duman RS (2010) Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35:2378–2391PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Siuciak JA, Lewis DR, Wiegand SJ, Lundsay R (1997) Antidepressant-like effect of brain derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56:131–137PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    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 22:3251–3261PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Sirianni RW, Olausson P, Chiu AS, Taylor JR, Saltzman WM (2010) The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats. Brain Res 1321:40–50PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A et al (2003) Activation of the TrkB neurotrophic receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349–357PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, Meuth S, Nagy A et al (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101:10827–10832PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M et al (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140–143PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    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 7:14926PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Marsden WN (2013) Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropscyhopharmacol Biol Psychiatry 43:168–184CrossRefGoogle Scholar
  112. 112.
    Boggio EM, Putignano E, Sassoe-Pognetto M, Pizzorusso T, Glustetto M (2007) Visual stimulation activates ERK in synaptic and somatic compartments of rat cortical neurons with parallel kinetics. PLoS One 2:e604PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Casar B, Arozarena I, Sanz-Moreno V, Pinto A, Agudo-Ibanez L, Marais R, Lewis RE, Berciano MT et al (2009) MTRas subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol Cell Biol 29:1338–1353PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Ortiz J, Harris HW, Guitart X, Terwilliger RZ, Haycock JW, Nestler EJ (1995) Extracellular signal-regulated protein kinases (ERKs) and ERK kinase (MEK) in brain: regional distribution and regulation by chronic morphine. J Neurosci 15:1285–1297PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Mao LM, Reusch JM, Fibuch EE, Liu Z, Wang JQ (2013) Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex. Brain Res 1494:101–108PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Suzuki T, Mitake S, Murata S (1999) Presence of up-stream and downstream components of a mitogen-activated protein kinase pathway in the PSD of the rat forebrain. Brain Res 840:36–44PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Suzuki T, Okumura-Noji K, Nishida E (1995) ERK2-type mitogen-activated protein kinase (MAPK) and its substrates in postsynaptic density fractions from the rat brain. Neurosci Res 22:277–285PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical SciencesUniversity of Missouri-Kansas City, School of MedicineKansas CityUSA
  2. 2.Department of AnesthesiologyUniversity of Missouri-Kansas City, School of MedicineKansas CityUSA

Personalised recommendations