Major depression is a serious side effect of interferon-α (IFN-α), which is used in the therapy of hepatitis C virus (HCV) infection. Due to the lack of reproducible animal models, the mechanisms underlying IFN-α-related depression are largely unknown. We herein established a mouse model, in which murine IFN-α (250 IU/day) and polyinosinic/polycytidylic acid (poly(I:C); 1 μg/day), a toll-like receptor-3 (TLR3) agonist that mimics the effect of HCV double-strand RNA, were continuously infused into the lateral ventricle via miniosmotic pumps over up to 14 days. The delivery of IFN-α and poly(I:C), but not of IFN-α or poly(I:C) alone, resulted in a reproducible depression-like state that was characterized by reduced exploration behavior in open-field tests, increased immobility in tail suspension and forced swimming tests, and a moderate loss of body weight. In the hippocampus and prefrontal cortex, the pro-inflammatory genes TNF-α, IL-6, tissue inhibitor of metalloproteinases-1 (Timp-1), CXC motif ligand-1 (Cxcl1), Cxcl10, and CC motif ligand-5 (Ccl5) were synergistically induced by IFN-α and poly(I:C), most pronounced after 14-day exposure. In comparison, the interferon-inducible genes of signal transducer and activator of transcription-1 (Stat1), guanylate binding protein-1 (Gbp1), proteasome subunit-β type-9 (Psmb9), ubiquitin-conjugating enzyme E2L-6 (Ube2l6), receptor transporter protein-4 (Rtp4), and GTP cyclohydrolase-1 (Gch1), which had previously been elevated in the blood of IFN-α-treated patients developing depression, in the brains of suicidal individuals, and in primary neurons exposed to IFN-α and poly(I:C), were induced even earlier, reaching maximum levels mostly after 24 hours. We propose that interferon-inducible genes might be useful markers of imminent depression.
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We want to thank Mrs. Kathrin Kleinehr and Mrs. Lena Poggenpohl for excellent technical assistance and to outline the exceptional help of Mr. Anthony Squire, manager of the Imaging Facility of the Clinic hospital of Essen, in the acquisition and analysis of the pictures.
Conflict of Interest
The authors declare that they have no conflict of interest.
Carolina Hoyo-Becerra, Zijian Liu, Dirk M. Hermann, and Joerg F. Schlaak contributed equally to this work.
Electronic supplementary material
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Dose-response evaluation of mIFN-α and poly(I:C) following intracerebroventricular delivery. Response of the interferon response gene Stat1 in the hippocampus and prefrontal cortex 24 h after intracerebroventricular infusion of mIFN-α or poly(I:C). Data are copy numbers, evaluated by RT-PCR, that were normalized with the house-keeping gene β-actin. Based on the concentration yielding the maximum response, EC25 doses (250 IU mIFN-α), 1 μg poly(I:C)) were determined that were used as daily doses in subsequent experiments. Data are mean values ± S.E.M. (PDF 119 kb)
Mild body weight loss as correlate of depressive phenotype in mice receiving combined mIFN-α and poly(I:C) exposure. Change of mouse body weight during 14 days exposure to mIFN-α (250 IU/day), poly(I:C) (1 μg/day) or both. Data are mean values ± S.E.M., evaluated by oneway ANOVA followed by Tukey’s posthoc tests (n = 12 animals per group). **p ≤ 0.05 compared with vehicle. (PDF 69 kb)
DRIIs without response to combined intracerebroventricular mIFN-α and poly(I:C) exposure. Fold changes of Tnfsf10, Mef2a and Dynlt1 mRNA in total RNA extracts isolated from the hippocampus (HP) and prefrontal cortex (PC) of mice after 24 h or 14 days exposure to mIFN (250 IU/day), poly(I:C) (1 μg/day) or both, as evaluated by RT-PCR. Data are mean values ± S.E.M. (n = 6 animals per group). No significant differences were found in oneway ANOVA followed by Tukey’s posthoc tests. (PDF 198 kb)
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Hoyo-Becerra, C., Liu, Z., Yao, J. et al. Rapid Regulation of Depression-Associated Genes in a New Mouse Model Mimicking Interferon-α-Related Depression in Hepatitis C Virus Infection. Mol Neurobiol 52, 318–329 (2015). https://doi.org/10.1007/s12035-014-8861-z
- TLR3 activation
- Interferon-inducible genes