Journal of Molecular Neuroscience

, Volume 69, Issue 2, pp 254–263 | Cite as

Interleukine-17 Administration Modulates Adult Hippocampal Neurogenesis and Improves Spatial Learning in Mice

  • Matanel Tfilin
  • Gadi TurgemanEmail author


Adult hippocampal neurogenesis plays an important role in health and disease. Regulating neurogenesis may be a key mechanism in the pathophysiology and treatment of several neurobehavioral disorders such as schizophrenia, depression, autism spectrum disorders and Alzheimer’s disease. Cytokines are known to affect adult neurogenesis, but conflicting studies have been reported with regard to their actual role. Interleukine-17 (IL-17), a potent pro-inflammatory cytokine, has been shown to inhibit proliferation of neuroprogenitors and thus reduce hippocampal neurogenesis, while other studies suggested it can promote neurite outgrowth. In the present study we sought to explore the possible effect of a single dose administration of IL-17 on neurogenesis related behavior, i.e. spatial learning. Surprisingly, ICR mice injected with IL-17 (8 μg) had a significant slight improvement in spatial learning in the Morris water maze paradigm, without any changes in general locomotion compared with control mice. Indeed, the expression of neurogenesis related genes was down regulated following IL-17 treatment. However, we detected an upregulation in the expression of FGF-13, a gene promoting microtubule polymerization and neurite outgrowth, thus supporting neuronal maturation. We thus suggest that IL-17 has a complex role in regulating adult neurogenesis: inhibiting neuroprogenitors proliferation on one hand, while promoting maturation of already formed neuroblasts on the other hand. Our findings suggest that these roles can potentially affect neurogenesis related behavior. Its actual role in health and disease is yet to be determined.


Interleukine-17A (IL-17A) Neurogenesis Spatial learning Fibroblat growth factor-13 Hippocampus 


Compliance with Ethical Standards

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.


  1. Abookasis D, Lerman D, Roth H, Tfilin M, Turgeman G (2018) Optically derived metabolic and hemodynamic parameters predict hippocampal neurogenesis in the BTBR mouse model of autism. J Biophotonics 11(3)Google Scholar
  2. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335CrossRefGoogle Scholar
  3. Asada M, Mizutani S, Takagi M, Suzuki H (2016) Antipsychotics promote neural differentiation of human iPS cell-derived neural stem cells. Biochem Biophys Res Commun 480(4):615–621CrossRefGoogle Scholar
  4. Benninghoff J, Grunze H, Schindler C, Genius J, Schloesser RJ, van der Ven A, Dehning S, Wiltfang J, Moller HJ, Rujescu D (2013) Ziprasidone--not haloperidol--induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus. Pharmacopsychiatry 46(1):10–15PubMedGoogle Scholar
  5. Beurel E, Harrington LE, Jope RS (2013) Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry 73(7):622–630CrossRefGoogle Scholar
  6. Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22(4):589–599 e585CrossRefGoogle Scholar
  7. Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–160CrossRefGoogle Scholar
  8. Chisholm SP, Cervi AL, Nagpal S, Lomax AE (2012) Interleukin-17A increases neurite outgrowth from adult postganglionic sympathetic neurons. J Neurosci 32(4):1146–1155CrossRefGoogle Scholar
  9. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY (2006) STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176(9):5652–5661CrossRefGoogle Scholar
  10. Dommasch ED, Li T, Okereke OI, Li Y, Qureshi AA, Cho E (2015) Risk of depression in women with psoriasis: a cohort study. Br J Dermatol 173(4):975–980CrossRefGoogle Scholar
  11. Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T (2014) The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Investig Dermatol 134(6):1542–1551CrossRefGoogle Scholar
  12. Faigle R, Song H (2013) Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 1830(2):2435–2448CrossRefGoogle Scholar
  13. Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229CrossRefGoogle Scholar
  14. Fitzsimons CP, van Bodegraven E, Schouten M, Lardenoije R, Kompotis K, Kenis G, van den Hurk M, Boks MP, Biojone C, Joca S, Steinbusch HW, Lunnon K, Mastroeni DF, Mill J, Lucassen PJ, Coleman PD, van den Hove DL, Rutten BP (2014) Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease. Mol Neurodegener 9:25CrossRefGoogle Scholar
  15. Fuster-Matanzo A, Llorens-Martin M, Hernandez F, Avila J (2013) Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediat Inflamm 2013:260925CrossRefGoogle Scholar
  16. Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438CrossRefGoogle Scholar
  17. Ghosal K, Stathopoulos A, Pimplikar SW (2010) APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One 5(7):e11866CrossRefGoogle Scholar
  18. Giachino C, Barz M, Tchorz JS, Tome M, Gassmann M, Bischofberger J, Bettler B, Taylor V (2014) GABA suppresses neurogenesis in the adult hippocampus through GABAB receptors. Development 141(1):83–90CrossRefGoogle Scholar
  19. Gobshtis N, Tfilin M, Wolfson M, Fraifeld VA, Turgeman G (2017) Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid. Oncotarget 8(11):17443–17452CrossRefGoogle Scholar
  20. Habash T, Saleh A, Roy Chowdhury SK, Smith DR, Fernyhough P (2015) The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol 273:177–189CrossRefGoogle Scholar
  21. Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131(22):5539–5550CrossRefGoogle Scholar
  22. Himmerich H, Schonherr J, Fulda S, Sheldrick AJ, Bauer K, Sack U (2011) Impact of antipsychotics on cytokine production in-vitro. J Psychiatr Res 45(10):1358–1365CrossRefGoogle Scholar
  23. Inestrosa NC, Varela-Nallar L (2015) Wnt signalling in neuronal differentiation and development. Cell Tissue Res 359(1):215–223CrossRefGoogle Scholar
  24. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101(1):343–347CrossRefGoogle Scholar
  25. Kabos P, Kabosova A, Neuman T (2002) Blocking HES1 expression initiates GABAergic differentiation and induces the expression of p21(CIP1/WAF1) in human neural stem cells. J Biol Chem 277(11):8763–8766CrossRefGoogle Scholar
  26. Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14(2):186–191CrossRefGoogle Scholar
  27. Keohane A, Ryan S, Maloney E, Sullivan AM, Nolan YM (2010) Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: role of Hes1. Mol Cell Neurosci 43(1):127–135CrossRefGoogle Scholar
  28. Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A 107(6):2669–2674CrossRefGoogle Scholar
  29. Li GZ, Zhong D, Yang LM, Sun B, Zhong ZH, Yin YH, Cheng J, Yan BB, Li HL (2005) Expression of interleukin-17 in ischemic brain tissue. Scand J Immunol 62(5):481–486CrossRefGoogle Scholar
  30. Li Z, Li K, Zhu L, Kan Q, Yan Y, Kumar P, Xu H, Rostami A, Zhang GX (2013) Inhibitory effect of IL-17 on neural stem cell proliferation and neural cell differentiation. BMC Immunol 14:20CrossRefGoogle Scholar
  31. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107(4):603–613CrossRefGoogle Scholar
  32. Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437(7063):1370–1375CrossRefGoogle Scholar
  33. Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18(19):7768–7778CrossRefGoogle Scholar
  34. Liu Q, Xin W, He P, Turner D, Yin J, Gan Y, Shi FD, Wu J (2014) Interleukin-17 inhibits adult hippocampal neurogenesis. Sci Rep 4:7554CrossRefGoogle Scholar
  35. Malakouti M, Brown GE, Wang E, Koo J, Levin EC (2015) The role of IL-17 in psoriasis. J Dermatol Treat 26(1):41–44CrossRefGoogle Scholar
  36. Mathieu P, Piantanida AP, Pitossi F (2010) Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation 17(3):200–201CrossRefGoogle Scholar
  37. Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5(2):101–104CrossRefGoogle Scholar
  38. Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, San Emeterio J, Hortiguela R, Marques-Torrejon MA, Nakashima K, Colak D, Gotz M, Farinas I, Gage FH (2010) Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell 7(1):78–89CrossRefGoogle Scholar
  39. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765CrossRefGoogle Scholar
  40. Perez-Asensio FJ, Perpina U, Planas AM, Pozas E (2013) Interleukin-10 regulates progenitor differentiation and modulates neurogenesis in adult brain. J Cell Sci 126(Pt 18):4208–4219CrossRefGoogle Scholar
  41. Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357CrossRefGoogle Scholar
  42. Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10(9):1110–1115CrossRefGoogle Scholar
  43. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192(2):348–356CrossRefGoogle Scholar
  44. Schreiber R, Newman-Tancredi A (2014) Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation. Neurobiol Learn Mem 110:72–80CrossRefGoogle Scholar
  45. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15(8):946–950CrossRefGoogle Scholar
  46. Solecki DJ, Liu XL, Tomoda T, Fang Y, Hatten ME (2001) Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31(4):557–568CrossRefGoogle Scholar
  47. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172(1):146–155CrossRefGoogle Scholar
  48. Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486–492CrossRefGoogle Scholar
  49. Wong H, Hoeffer C (2018) Maternal IL-17A in autism. Exp Neurol 299(Pt A):228–240CrossRefGoogle Scholar
  50. Wu QF, Yang L, Li S, Wang Q, Yuan XB, Gao X, Bao L, Zhang X (2012) Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration. Cell 149(7):1549–1564CrossRefGoogle Scholar
  51. Yang J, Jiang Z, Fitzgerald DC, Ma C, Yu S, Li H, Zhao Z, Li Y, Ciric B, Curtis M, Rostami A, Zhang GX (2009) Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. J Clin Invest 119(12):3678–3691CrossRefGoogle Scholar
  52. Yilmaz SB, Cicek N, Coskun M, Yegin O, Alpsoy E (2012) Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. Arch Dermatol Res 304(6):465–469CrossRefGoogle Scholar
  53. Zhang Z, Yan R, Zhang Q, Li J, Kang X, Wang H, Huan L, Zhang L, Li F, Yang S, Zhang J, Ren X, Yang X (2014) Hes1, a notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury. Brain Res 1583:65–78CrossRefGoogle Scholar
  54. Zhou J, Nagarkatti P, Zhong Y, Ginsberg JP, Singh NP, Zhang J, Nagarkatti M (2014) Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 9(4):e94075CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Departments of Molecular Biology and Pre-Medical StudiesAriel UniversityArielIsrael

Personalised recommendations