Research reportCognitive function in young and adult IL (interleukin)-6 deficient mice
Introduction
Interleukin-6 (IL-6) is a plurifunctional cytokine implicated in the regulation of multiple aspects of immune response, haemopoiesis and inflammation [26], [43]. In addition to its essential role in the function of immune system, it is present in the CNS, where it is constitutively expressed in different cell types and where specific binding sites have been found [21].
Circulating IL-6 may exert neurochemical modifications in different mouse brain regions, such as the hippocampus, the hypothalamus and prefrontal cortex [7], [44]. IL-6 can induce completely opposite actions on neurons, triggering either neuronal survival after injury or causing neuronal degeneration and cell death in disorders such as Alzheimer’s disease [24].
A pathological role for IL-6 on developing CNS neurons using a culture model [22] and a chronic treatment paradigm has been reported [35]. Several studies implicate IL-6 as an important mediator in the development of neurologic disorders including AIDS dementia and Alzheimer’s disease [4].
Furthermore, overexpression of IL-6 in the brain of transgenic mice (GFAP-IL6) has been shown to cause severe neurological disease, a progressive decline in avoidance learning [14], [23] and a reduced long-term potentiation (LTP) in the dentate gyrus [5]. In 10 months old senescence accelerated prone mice, a murine model for accelerated aging, the protein levels of IL-6 in the hippocampus and cerebral cortex is markedly increased [40].
However, the role of IL-6 does not appear to be restricted to pathological conditions, since it is expressed in the normal brain, is developmentally regulated, has neurotrophic effects and is involved in the control of emotionality [3], [13], [14], [28], [30] and general behaviour [1].
About the involvement of IL-6 on memory functions, little is known and the evidence obtained often contradictory. An improvement of scopolamine-induced cognitive deficit was observed in mice peripherally treated with human recombinant IL-6 (0.125 and 0.5 μg per mouse). This effect was not accompanied by changes in hippocampal levels of glutamine, aspartic acid, glutamate and GABA [8], [11]. Furthermore, when continuously infused into the lateral ventricles of gerbils with 3-min forebrain ischemia, IL-6 prevented the occurrence of learning disability and hippocampal neuron loss [31]. However, in another study, Clark et al. [15] found that the response to ischemic injury was the same in animals lacking IL-6 as in matched controls. Bilateral infusion of IL-6 into the rat hippocampus impaired retention using passive avoidance test [29].
In order to better understand the role of IL-6 on CNS function, we investigated cognitive functions in transgenic male mice not expressing IL-6.
Reference memory was studied using passive avoidance test, classically employed for the evaluation of drugs that interfere with cognitive functions in experimental animals [16] in absence or in presence of scopolamine. Working memory was tested in an eight-arm radial maze, a specific learning task that depends on intact hippocampus [33]. Ultimately, because cholinergic system plays an important role in hippocampal memory [39] the choline acetyltransferase (ChAT) activity was analysed in this brain area of wild type (WT) and IL-6 knock out (KO) mice.
Section snippets
Animals
In order to obtain IL-6 deficient mice and to abolish IL-6 function, the sequence coding for the amino-terminal half of the protein was eliminated. ES cell clones (129 type, from the ES cell line CCE, see [37]) carrying the IL-6 mutation were injected into blastocysts of C57BL6 mice and transplanted into the uteri of F1 (CBA×C57BL6) foster mothers. Male chimeras were mated to MFI strain females and agouti offspring (representing germline transmission of the ES genome), were screened for the
Passive avoidance
Fig. 1 reports the passive avoidance response of 4-month-old WT and IL-6 KO mice. The passive avoidance response was different between groups [F(3,36)=74.58, P<0.001]. Both genotypes did not differ in response latency when given vehicle. The scopolamine-induced cognitive deficit was significantly different between WT and IL-6 KO mice (P<0.001). In fact, IL-6 KO mice showed a greater latency as compared with WT genotype. However, IL-6 KO mice given scopolamine had a retention latency
Discussion
The main results of the present study show that IL-6 deficiency leads to a facilitatory effect on learning and memory suggesting an important role of this cytokine in brain function.
The results of the passive avoidance test suggest that IL-6 interacts with cholinergic system. In fact, even if IL-6 deficient mice did not show, under basal conditions, an increase in the step-through latency in comparison to WT, however they exhibited a reduced amnesic effect of scopolamine. This reduction seems
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2021, Brain, Behavior, and Immunity - HealthCitation Excerpt :Similarly, also intracerebroventricular injection of pro-inflammatory cytokines has been shown to impair spatial memory processes (Oitzl et al., 1993; Gibertini et al., 1995; Song and Horrobin, 2004), while superfusing hippocampal brain slices with pro-inflammatory cytokines is reported to inhibit hippocampal synaptic strength and LTP (Katsuki et al., 1990; Bellinger et al., 1993). In addition, an array of genetic studies yielded compelling evidence that transgenic mice with hippocampal over-expression of IL-1 (Moore et al., 2009; Hein et al., 2010) or TNF-α (Fiore et al., 2000) exhibit impaired spatial memory performance, while knockout-mice lacking IL-6 (Braida et al., 2004) or TNF-α (Golan et al., 2004) show improved spatial memory performance. Intriguingly, the impairing effects of inflammation on hippocampus-dependent spatial memory are thought to be modifiable, as indicated by several animal studies which demonstrated that exposure to anti-inflammatory agents attenuates the adverse effects of inflammation on spatial memory, and even improves spatial memory (Ormerod et al., 2013; Wadhwa et al., 2017a; Cui et al., 2008; Marchalant et al., 2008; He et al., 2011; Kumar et al., 2018).