Skip to main content

Advertisement

Log in

Hippocampus-specific deficiency of IL-15Rα contributes to greater anxiety-like behaviors in mice

  • Short Communication
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

A hippocampus-specific IL15RαKO mouse (hipIl15ra fl/fl/Cre+) was generated to test the hypothesis that the targeted deletion of interleukin-15 receptor alpha (IL-15Rα) in the hippocampus contributes to altered behavior, including greater levels of anxiety and ambulatory activity. Using Cre-loxP, exons 2 and 3 of the IL-15Rα gene were excised within the hippocampus, while normal expression was maintained within the rest of the brain. In the open field test (OFT), hipIl15ra fl/fl/Cre+ spent a greater amount of time in the periphery and less time in the central portions of the chamber, and there was also a noticeable trend for decreased rearing activity; these behaviors are consistent with greater levels of anxiety-like behavior in these mice. However, there were no differences in the overall locomotor counts in the OFT when comparing hipIl15ra fl/fl/Cre+ mice to their littermate controls. These data implicate IL-15-related signaling within the hippocampus has a role in anxiety-like behavior.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

References

  • Bamford RN, Battiata AP, Burton JD, Sharma H, Waldmann TA (1996) Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation. Proc Natl Acad Sci U S A 93:2897–2902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergamaschi C et al (2008) Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. J Biol Chem 283:4189–4199

    Article  CAS  PubMed  Google Scholar 

  • Costall B, Jones BJ, Kelly ME, Naylor RJ, Tomkins DM (1989) Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 32:777–785

    Article  CAS  PubMed  Google Scholar 

  • Ennaceur A (2014) Tests of unconditioned anxiety - pitfalls and disappointments. Physiol Behav 135:55–71. doi:10.1016/j.physbeh.2014.05.032

    Article  CAS  PubMed  Google Scholar 

  • Giri JG et al (1994) Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13:2822–2830

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giri JG et al (1995) Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J 14:3654–3663

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grabstein KH et al (1994) Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science (New York, NY) 264:965–968

    Article  CAS  Google Scholar 

  • He Y et al (2010) IL-15 receptor deletion results in circadian changes of locomotor and metabolic activity. J Mol Neurosci 41:315–321

    Article  CAS  PubMed  Google Scholar 

  • Kubota T, Brown RA, Fang J, Krueger JM (2001) Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits. Am J Phys 281:R1004–R1012

    CAS  Google Scholar 

  • Li YF, Huang Y, Amsdell SL, Xiao L, O’Donnell JM, Zhang HT (2009) Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 34:2404–2419 doi:10.1038/npp.2009.66

  • Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669–676

    Article  CAS  PubMed  Google Scholar 

  • Masood A, Nadeem A, Mustafa SJ, O’Donnell JM (2008) Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. J Pharmacol Exp Ther 326:369–379 doi:10.1124/jpet.108.137208

  • Mortier E et al (2009) Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets. Immunity 31:811–822

    Article  CAS  PubMed  Google Scholar 

  • O’Connell GC, Pistilli EE (2015a) Interleukin-15 directly stimulates pro-oxidative gene expression in skeletal muscle in-vitro via a mechanism that requires interleukin-15 receptor alpha. Biochem Biophys Res Commun 458:614–619. doi:10.1016/j.bbrc.2015.02.015

    Article  PubMed  Google Scholar 

  • O’Connell G, Guo G, Stricker J, Quinn LS, Ma A, Pistilli EE (2015) Muscle-specific deletion of exons 2 and 3 of the IL15RA gene in mice: effects on contractile properties of fast and slow muscles. J Appl Physiol 118:437–448 doi:10.1152/japplphysiol.00704.2014

  • O’Connell GC, Nichols C, Guo G, Croston TL, Thapa D, Hollander JM, Pistilli EE (2015b) IL-15Ralpha deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome. Mitochondrion 25:87–97. doi:10.1016/j.mito.2015.10.004

    Article  PubMed  PubMed Central  Google Scholar 

  • Pan W, Wu X, He Y, Hsuchou H, Huang EY, Mishra PK, Kastin AJ (2013) Brain interleukin-15 in neuroinflammation and behavior. Neurosci Biobehav Rev 37:184–192. doi:10.1016/j.neubiorev.2012.11.009

    Article  CAS  PubMed  Google Scholar 

  • Pistilli EE, Quinn LS (2013) From anabolic to oxidative: reconsidering the roles of IL-15 and IL-15Ralpha in skeletal muscle. Exerc Sport Sci Rev 41:100–106. doi:10.1097/JES.0b013e318275d230

    Article  PubMed  PubMed Central  Google Scholar 

  • Pistilli EE, Siu PM, Alway SE (2007) Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy. Am J Physiol Cell Physiol 292:C1298–C1304. doi:10.1152/ajpcell.00496.2006

    Article  CAS  PubMed  Google Scholar 

  • Pistilli EE et al (2011) Loss of IL-15 receptor alpha alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 121:3120–3132. doi:10.1172/JCI44945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pistilli EE, Guo G, Stauber WT (2013) IL-15Ralpha deficiency leads to mitochondrial and myofiber differences in fast mouse muscles. Cytokine 61:41–45. doi:10.1016/j.cyto.2012.09.025

    Article  CAS  PubMed  Google Scholar 

  • Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T, Marcell TJ (2014) IL-15 is required for postexercise induction of the pro-oxidative mediators PPARdelta and SIRT1 in male mice. Endocrinology 155:143–155. doi:10.1210/en.2013-1645

    Article  PubMed  Google Scholar 

  • Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, Sprent J (2006) Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A 103:9166–9171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Pan W, Stone KP, Zhang Y, Hsuchou H, Kastin AJ (2010) Expression and signaling of novel IL15Ralpha splicing variants in cerebral endothelial cells of the blood-brain barrier. J Neurochem 114:122–129. doi:10.1111/j.1471-4159.2010.06729.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X et al (2011) Interleukin-15 affects serotonin system and exerts antidepressive effects through IL15Ra receptor. Psychoneuroendocrinology 36:266–278

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The experiments presented in this manuscript were supported by New Faculty Start-Up funds through West Virginia University (E.E. Pistilli).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emidio E. Pistilli.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, L., Bohlen, J., Stricker, J. et al. Hippocampus-specific deficiency of IL-15Rα contributes to greater anxiety-like behaviors in mice. Metab Brain Dis 32, 297–302 (2017). https://doi.org/10.1007/s11011-016-9930-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-016-9930-y

Keywords

Navigation