title: Rapid Regulation of Depression-Associated Genes in a New Mouse Model Mimicking Interferon-α-Related Depression in Hepatitis C Virus Infection.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Hoyo-Becerra
authors.forename: Zijian
authors.initials: Z
authors.lastname: Liu
authors.forename: Jinghong
authors.initials: J
authors.lastname: Yao
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D003863:Depression / Q000139:chemically induced* / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy*; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000009:adverse effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018925:Chemokines; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D010447:Peptide Hydrolases; D011070:Poly I-C