Blocking interleukin-1 signalling in the brain-structural and functional outcomes

Abstract

The aims of this thesis were to evaluate the consequences of blocking interleukin (IL)-1 signalling in the brain. The studies used a transgenic mouse model with brain-directed overexpression of the human soluble isoform of IL-1 receptor antagonist with the GFAP promoter (Tg hsIL-1ra).

In the first study we investigated the impact of blocking IL-1 signalling in the brain, and we found no compensatory increase in expression of proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha). Moreover, ageing had a much stronger effect on cytokine expression than blocking IL-1 signalling per se.Similarly, we found that APP and PS1 levels varied in opposite directions with ageing in both transgenic and WT animals. Direct volumetric measurements showed that Tg hsIL-1ra mice have smaller brains than age-matched wild-type (WT) animals.

In the second study we analysed the role of IL-1 signalling in regulating neurogenesis and gliosis. The experimental setting consisted of either acute (seizures) or chronic (ageing) neuroinflammation. We found that overexpressing hsIL-ra in the brain impairs the generation of new neurones in the subgranular zone of the dentate gyrus, and that the step most tightly controlled by IL-1 is the terminal neuronal differentiation. Similarly, blocking IL-1 signalling resulted in much attenuated variations in the levels of expression of glial activation markers in both acute and chronic neuroinflammation. In addition, the Tg hsIL-1ra mice displayed higher levels of microglial activation markers under basal conditions, but no variations either following seizures or in ageing as compared to WT mice.

For the third study we used both littermate and non-littermate mice in order to control for the effect of prenatal exposure to hsIL-1ra, and analysed the behavioural profile at the ages of 6 and 12 months, as well as the morphology of the brain at 12 months of age. Multivariate data analysis was used for detecting significant separation according to the genotype (WT vs. Tg hsIL-1ra) and parenting (littermates vs. non-littermates), as well as for studying the correlation between brain morphology and behavioural pattern. We found that continuous overexpression of hsIL-1ra in the brain results in an altered behavioural profile characterised by lower anxiety and higher exploratory activity. The prenatal exposure to hsIL-1ra induced alterations in the behavioural pattern detectable at the age of 6 months, but not at 12 months. The differences in brain morphology explained most of the altered behavioural profile, and the brain-restricted overexpression of hsIL-1ra and the prenatal exposure to the transgene product had cumulative effects.

In the fourth study we investigated the mechanisms by which interfering with IL-1 signalling results in learning deficits. We found that the consolidation of long-term memory is impaired both in the dentate gyrus and in the retrosplenial cortex. The underlying mechanisms are related to synaptic consolidation, including BDNF expression and synaptic plasticity.

In conclusion, we have shown that IL-1 signalling is essential for the appropriate development of the brain, but its blocking does not result in compensatory increase in the expression of proinflammatory cytokines in the adult brain. IL-1 is also playing an important role in synaptic plasticity, and the deficit induced by prenatal exposure to IL-1ra results in an altered behavioural profile that can be recovered from, provided the IL-1 signalling is intact.