Analysis of genes linked to depressive-like behaviors in interleukin-18-deficient mice: Gene expression profiles in the brain

Abstract

Interleukin (IL)-18 is an interferon γ-inducing inflammatory cytokine associated with function of the immune system and other physiological functions. IL-18-deficient (Il18-/-) mice exhibit obesity, dyslipidemia, non-alcoholic steatohepatitis and depressive-like behavioral changes. Therefore, IL-18 has a number of important roles associated with immunity, energy homeostasis and psychiatric conditions. In the present study, gene expression in the brains of Il18-/- mice was analyzed to identify genes associated with the depressive-like behaviors and other impairments displayed by Il18-/- mice. Using whole genome microarray analysis, gene expression patterns in the brains of Il18+/+ and Il18-/- mice at 6 and 12 weeks of age were examined and compared. Subsequently, genes were categorized using Ingenuity® Pathway Analysis (IPA). At 12 weeks of age, 2,805 genes were identified using microarray analysis. Genes related to ‘Major depression’ and ‘Depressive disorders’ were identified by IPA core analysis, and 13 genes associated with depression were isolated. Among these genes, fibroblast growth factor receptor 1 (Fgfr1); protein tyrosine phosphatase, non-receptor type 1 (Ptpn1); and urocortin 3 (Ucn3) were classed as depression-inducing and the other genes were considered depression-suppressing genes. Subsequently, the interactions between the microarray results at 6 weeks of age and the above three depression-inducing genes were analyzed to search for effector genes of depression at 12 weeks of age. This analysis identified cyclin D1 (Ccnd1) and NADPH oxidase 4 (Nox4). The microarray analysis results were correlated with the results of reverse transcription-quantitative PCR (RT-qPCR). Overall, the results suggest that Fgfr1, Ptpn1 and Ucn3 may be involved in depression-like changes and Ccnd1 and Nox4 regulate these three genes in IL-18-deficient mice.