Genetic exploration of novel behavioral phenotypes in interleukin-7 and interleukin-18 receptor knockout mice

Knockout mice are widely used in biomedical research. Gene targeting technology necessitates transferring the null mutation from one strain to another; therefore, some genetic material is carried with the gene mutation onto the recipient genetic background. This issue complicates knockout studies, but also provides an opportunity for genetic mapping of complex traits. Here, we analyzed interleukin-7 alpha receptor (Il7r-/-; B6.129S7- Il7rtm1Imx/J) and interleukin-18 alpha receptor (Il18r -/-; B6.129P2-Il18r1tm1Aki/J) knockout/congenic strains to elucidate the genetic underpinnings of learning and memory, ambulation, and anxiety-related behaviors.;Il7r-/- mice display recessive deficits in habituation and ambulation in the open field. Earlier evidence suggested that Il7r is responsible for these deficits; however, we identified a second Il7r-/- cohort that behaves like C57BL/6J (B6/J) controls. Increased anxiety levels during the initial testing session may explain the failure of Il7r-/- mice to habituate, as Il7r-/- home cage ambulation is similar to controls. We conclude that Il7r -/- mice show increased sensitivity to anxiety-inducing stimuli. While Il7r alone does not produce the observed phenotypes, Il7r may influence the phenotypes via epistatic interactions with other loci. Based upon genetic variability at non-B6/J loci and differential gene expression between Il7r-/- cohorts, we identified behavioral candidate genes with roles in vesicular transport, RNA stability, and gene silencing.;Il18r-/- mice exhibit a recessive deficit in ambulatory activity in the open field that does not appear to be influenced by anxiety or physical limitations. This phenotype appears to be due to 129P2-derived genetic material. We investigated the possibility that sickness behavior underlies theIl18r-/- activity deficit by administering lipopolysaccharide (LPS. We assessed LPS-induced effects on ambulation and inflammatory cytokine profiles in brain regions involved in behavioral and immune responses. These data suggest that LPS induces neuroinflammation and sickness behavior similarly for each strain. Thus, the absence of IL-18 or its receptor does not appear to disrupt the proinflammatory cytokine cascade.;Our data show that phenotype differences can result from background genetic differences rather than from loss of the targeted gene in a knockout/congenic strain, as investigators generally assume. These studies highlight the importance of investigating the genetic background of knockout mice to avoid misinterpretation of results.