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Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects

Molecular Psychiatry volume 25, pages 1260–1274 (2020)Cite this article

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Abstract

Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)—MBP87–99[A91, A96], MBP87–99[A91], and MBP87–99[R91, A96]—in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87–99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87–99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87–99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87–99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87–99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune–neural interactions may impact central nervous system function and alter an individual’s response to stress.

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References

  1. Martinowich K, Jimenez DV, Zarate CA Jr., Manji HK. Rapid antidepressant effects: moving right along. Mol Psychiatry. 2013;18:856–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  PubMed  Google Scholar 

  3. Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci. 2015;18:1386–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.

    Article  CAS  PubMed  Google Scholar 

  5. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21:1696–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167–73.

    Article  CAS  PubMed  Google Scholar 

  7. Sutcigil L, Oktenli C, Musabak U, Bozkurt A, Cansever A, Uzun O, et al. Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy. Clin Dev Immunol. 2007;2007:76396.

    Article  PubMed  Google Scholar 

  8. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet. 2002;360:1831–7.

    Article  CAS  PubMed  Google Scholar 

  9. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.

    Article  CAS  PubMed  Google Scholar 

  10. Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21:1358–65.

    Article  CAS  PubMed  Google Scholar 

  11. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66:407–14.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. D’Mello C, Swain MG. Immune-to-brain communication pathways in inflammation-associated sickness and depression. Curr Top Behav Neurosci. 2017;31:73–94.

    Article  PubMed  CAS  Google Scholar 

  14. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA. 2011;108:9262–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, et al. Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology. 2001;24:531–44.

    Article  CAS  PubMed  Google Scholar 

  16. Alboni S, Benatti C, Montanari C, Tascedda F, Brunello N. Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus. Eur J Pharm. 2013;721:158–67.

    Article  CAS  Google Scholar 

  17. Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30.

    Article  CAS  PubMed  Google Scholar 

  18. Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Katsara M, Deraos G, Tselios T, Matsoukas MT, Friligou I, Matsoukas J, et al. Design and synthesis of a cyclic double mutant peptide (cyclo(87-99)[A91,A96]MBP87-99) induces altered responses in mice after conjugation to mannan: implications in the immunotherapy of multiple sclerosis. J Med Chem. 2009;52:214–8.

    Article  CAS  PubMed  Google Scholar 

  20. Karin N, Mitchell DJ, Brocke S, Ling N, Steinman L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med. 1994;180:2227–37.

    Article  CAS  PubMed  Google Scholar 

  21. Tselios T, Apostolopoulos V, Daliani I, Deraos S, Grdadolnik S, Mavromoustakos T, et al. Antagonistic effects of human cyclic MBP(87-99) altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation. J Med Chem. 2002;45:275–83.

    Article  CAS  PubMed  Google Scholar 

  22. Gaur A, Boehme SA, Chalmers D, Crowe PD, Pahuja A, Ling N, et al. Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms. J Neuroimmunol. 1997;74:149–58.

    Article  CAS  PubMed  Google Scholar 

  23. Smilek DE, Wraith DC, Hodgkinson S, Dwivedy S, Steinman L, McDevitt HO. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 1991;88:9633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, et al. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001;108:591–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen A, et al. Vaccination as a novel approach for treating depressive behavior. Biol Psychiatry. 2009;65:283–8.

    Article  PubMed  Google Scholar 

  26. Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci. 2013;14:673–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Svenningsson P, Greengard P. p11 (S100A10)–an inducible adaptor protein that modulates neuronal functions. Curr Opin Pharm. 2007;7:27–32.

    Article  CAS  Google Scholar 

  28. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80.

    Article  CAS  PubMed  Google Scholar 

  29. Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N. Identification of the cortical neurons that mediate antidepressant responses. Cell. 2012;149:1152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Seo JS, Wei J, Qin L, Kim Y, Yan Z, Greengard P. Cellular and molecular basis for stress-induced depression. Mol Psychiatry. 2017;22:1440–7.

    Article  CAS  PubMed  Google Scholar 

  32. Zhu WL, Wang SJ, Liu MM, Shi HS, Zhang RX, Liu JF, et al. Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci. 2013;38:306–16.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sukoff Rizzo SJ, Neal SJ, Hughes ZA, Beyna M, Rosenzweig-Lipson S, Moss SJ, et al. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl Psychiatry. 2012;2:e199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen Y, Chen J, Wen H, Gao P, Wang J, Zheng Z, et al. S100A10 downregulation inhibits the phagocytosis of Cryptococcus neoformans by murine brain microvascular endothelial cells. Micro Pathog. 2011;51:96–100.

    Article  CAS  Google Scholar 

  35. Jian M, Luo YX, Xue YX, Han Y, Shi HS, Liu JF, et al. eIF2alpha dephosphorylation in basolateral amygdala mediates reconsolidation of drug memory. J Neurosci. 2014;34:10010–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Li SX, Han Y, Xu LZ, Yuan K, Zhang RX, Sun CY, et al. Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry. 2018;23:597–608.

    Article  PubMed  CAS  Google Scholar 

  37. Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B, et al. Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology. 2013;38:1387–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shi HS, Zhu WL, Liu JF, Luo YX, Si JJ, Wang SJ, et al. PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3. Neuropsychopharmacology. 2012;37:2671–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Okamoto H, Voleti B, Banasr M, Sarhan M, Duric V, Girgenti MJ, et al. Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biol Psychiatry. 2010;68:521–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Han Y, Luo Y, Sun J, Ding Z, Liu J, Yan W, et al. AMPK signaling in the dorsal hippocampus negatively regulates contextual fear memory formation. Neuropsychopharmacology. 2016;41:1849–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xue YX, Chen YY, Zhang LB, Zhang LQ, Huang GD, Sun SC, et al. Selective inhibition of amygdala neuronal ensembles encoding nicotine-associated memories inhibits nicotine preference and relapse. Biol Psychiatry. 2017;82:781–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kafetzopoulos V, Kokras N, Sotiropoulos I, Oliveira JF, Leite-Almeida H, Vasalou A, et al. The nucleus reuniens: a key node in the neurocircuitry of stress and depression. Mol Psychiatry. 2018;23:579–86.

    Article  CAS  PubMed  Google Scholar 

  43. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Engler H, Brendt P, Wischermann J, Wegner A, Rohling R, Schoemberg T, et al. Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms. Mol Psychiatry. 2017;22:1448–54.

    Article  CAS  PubMed  Google Scholar 

  45. Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13:717–28.

    Article  CAS  PubMed  Google Scholar 

  46. Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009;40:139–56.

    Article  CAS  PubMed  Google Scholar 

  47. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Thomas AJ, Davis S, Morris C, Jackson E, Harrison R, O’Brien JT. Increase in interleukin-1beta in late-life depression. Am J Psychiatry. 2005;162:175–7.

    Article  PubMed  Google Scholar 

  49. Levine J, Barak Y, Chengappa KN, Rapoport A, Rebey M, Barak V. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology. 1999;40:171–6.

    Article  CAS  PubMed  Google Scholar 

  50. Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, Listwak SJ, et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab. 2005;90:2522–30.

    Article  CAS  PubMed  Google Scholar 

  51. Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol Psychiatry. 2015;78:38–48.

    Article  CAS  PubMed  Google Scholar 

  53. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Slyepchenko A, Maes M, Kohler CA, Anderson G, Quevedo J, Alves GS, et al. T helper 17 cells may drive neuroprogression in major depressive disorder: proposal of an integrative model. Neurosci Biobehav Rev. 2016;64:83–100.

    Article  CAS  PubMed  Google Scholar 

  55. Katsara M, Yuriev E, Ramsland PA, Tselios T, Deraos G, Lourbopoulos A, et al. Altered peptide ligands of myelin basic protein (MBP87-99) conjugated to reduced mannan modulate immune responses in mice. Immunology. 2009;128:521–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA. 2008;105:751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Goshen I, Yirmiya R. Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocr. 2009;30:30–45.

    Article  CAS  Google Scholar 

  58. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–6.

    Article  CAS  PubMed  Google Scholar 

  59. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–52.

    Article  CAS  PubMed  Google Scholar 

  60. Brymer KJ, Romay-Tallon R, Allen J, Caruncho HJ, Kalynchuk LE. Exploring the potential antidepressant mechanisms of TNFalpha antagonists. Front Neurosci. 2019;13:98.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Riga MS, Teruel-Marti V, Sanchez C, Celada P, Artigas F. Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex. Neuropharmacology. 2017;113:148–55.

    Article  CAS  PubMed  Google Scholar 

  62. Wu PR, Cho KK, Vogt D, Sohal VS, Rubenstein JL. The cytokine CXCL12 promotes basket interneuron inhibitory synapses in the medial prefrontal cortex. Cereb Cortex. 2017;27:4303–13.

    Article  PubMed  Google Scholar 

  63. Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell. 1989;59:247–55.

    Article  CAS  PubMed  Google Scholar 

  64. Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421–31.

    Article  CAS  PubMed  Google Scholar 

  66. Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511.

    Article  CAS  PubMed  Google Scholar 

  67. Pearson-Leary J, Zhao C, Bittinger K, Eacret D, Luz S, Vigderman AS, et al. The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 2019; https://doi.org/10.1038/s41380-019-0380-x. [Epub ahead of print]

    Article  PubMed  Google Scholar 

  68. Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, et al. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry. 2016;21:797–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl Psychiatry. 2017;7:e1138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Weiss R, Bitton A, Ben Shimon M, Elhaik Goldman S, Nahary L, Cooper I, et al. Annexin A2, autoimmunity, anxiety and depression. J Autoimmun. 2016;73:92–99.

    Article  CAS  PubMed  Google Scholar 

  71. Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P. Neurogenic effects of fluoxetine are attenuated inp11 (S100A10) knockout mice. Biol Psychiatry. 2010;67:1048–56.

    Article  CAS  PubMed  Google Scholar 

  72. Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee KW, Westin L, Kim J, Chang JC, Oh YS, Amreen B, et al. Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry. 2015;20:1546–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P, et al. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. J Neurosci. 2009;29:1937–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31:2121–31.

    Article  CAS  PubMed  Google Scholar 

  76. Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010;35:2510–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Linthorst AC, Flachskamm C, Muller-Preuss P, Holsboer F, Reul JM. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci. 1995;15:2920–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang J, Terreni L, De Simoni MG, Dunn AJ. Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochem Int. 2001;38:303–8.

    Article  CAS  PubMed  Google Scholar 

  79. Baganz NL, Lindler KM, Zhu CB, Smith JT, Robson MJ, Iwamoto H, et al. A requirement of serotonergic p38alpha mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors. Transl Psychiatry. 2015;5:e671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Huang XL, Pawliczak R, Yao XL, Cowan MJ, Gladwin MT, Walter MJ, et al. Interferon-gamma induces p11 gene and protein expression in human epithelial cells through interferon-gamma-activated sequences in the p11 promoter. J Biol Chem. 2003;278:9298–308.

    Article  CAS  PubMed  Google Scholar 

  81. Guo J, Zhang W, Zhang L, Ding H, Zhang J, Song C, et al. Probable involvement of p11 with interferon alpha induced depression. Sci Rep. 2016;6:17029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jansen R, Penninx BW, Madar V, Xia K, Milaneschi Y, Hottenga JJ, et al. Gene expression in major depressive disorder. Mol Psychiatry. 2016;21:339–47.

    Article  CAS  PubMed  Google Scholar 

  83. Svenningsson P, Berg L, Matthews D, Ionescu DF, Richards EM, Niciu MJ, et al. Preliminary evidence that early reduction in p11 levels in natural killer cells and monocytes predicts the likelihood of antidepressant response to chronic citalopram. Mol Psychiatry. 2014;19:962–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry. 2010;68:528–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Park SW, Nhu le H, Cho HY, Seo MK, Lee CH, Ly NN, et al. p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived primary hippocampal cells. J Affect Disord. 2016;196:1–10.

    Article  CAS  PubMed  Google Scholar 

  86. Werneburg S, Feinberg PA, Johnson KM, Schafer DP. A microglia-cytokine axis to modulate synaptic connectivity and function. Curr Opin Neurobiol. 2017;47:138–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (Nos. 81701312, 81871046, 81722018, and 81521063), National Basic Research Program of China (Nos. 2015CB856400, 2015CB559200, and 2015CB553503), Funds for Excellent PhD Graduates of Peking University Health Science Center (No. BMU20160569), the interdisciplinary medicine Seed Fund of Peking University (Nos. BMU2017MX022 and BMU2018MX024), and Beijing Brain Project (No. Z171100000117014).

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  1. These authors contributed equally: Ying Han, Cheng-Yu Sun, Shi-Qiu Meng

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  1. National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, 100191, Beijing, China

    Ying Han, Cheng-Yu Sun, Shi-Qiu Meng, Ling-Zhi Xu, Wei-Li Zhu, Jia-Li Li, Yan-Xue Xue & Jie Shi

  2. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China

    Cheng-Yu Sun, Wei Yan, Ling-Zhi Xu, Jia-Hui Deng & Lin Lu

  3. Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China

    Serik Tabarak, Kai Yuan, Lu Cao & Lin Lu

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Han, Y., Sun, CY., Meng, SQ. et al. Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects. Mol Psychiatry 25, 1260–1274 (2020). https://doi.org/10.1038/s41380-019-0470-9

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  • DOI: https://doi.org/10.1038/s41380-019-0470-9

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