Morphological and behavioral changes induced by transgenic overexpression of interleukin-1ra in the brain

Interleukin-1 (IL-1) has a peak of expression in the brain in a period of maximal network reorganization and then virtually disappears from the normal adult brain. The aim of our study was to identify phenotypical alterations induced by chronically blocking IL-1 signalling. We used homozygous transgenic mice overexpressing human soluble IL-1ra and age-matched wild-type mice. We used littermates from litters obtained by mating heterozygous transgenic progenitors, and animals with predetermined genotype (nonlittermates). In littermates, the genotype was identified after the experiments had been completed. The mice were tested at the ages of 6 and 12 months with a battery of tests, including dark-light preference, footprint/gait analysis, and analysis of motor performance during swimming. MR imaging was performed on formalin-fixed brains; total and relative volumes of cortical and subcortical structures were estimated stereologically on the acquired images. Multivariate data analysis (PLS-DA) of the behavioral data showed separation between nonlittermate wild-type and transgenic mice at both 6 and 12 months, whereas the littermates displayed a more homogenous behavioral profile. The PLS-DA model for brain morphology showed a clear separation between wild-type and transgenic mice as well as between transgenic littermates and nonlittermates. Regression analysis by means of partial least squares (PLS) showed that the brain morphology accounts for the behavioral profile in a significant proportion (16.9%). In conclusion, we show that IL-1 signalling is important for normal development of the brain, and the initial alteration resulting from prenatal exposure to IL-1ra can be recovered provided that the IL-1 signalling pathway is intact.