Behavioural Brain Research 153 (2004) 423–429 Research report Cognitive function in young and adult IL (interleukin)-6 deficient mice Daniela Braida a , Paola Sacerdote a , Alberto E. Panerai a , Mauro Bianchi a , Anna Maria Aloisi b , Stefania Iosuè a , Mariaelvina Sala a,∗ a Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32/A, 20129 Milan, Italy b Department of Physiology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy Received 7 November 2003; received in revised form 19 December 2003; accepted 19 December 2003 Available online 1 February 2004 Abstract Interleukin-6 (IL-6) is a cytokine shown to affect brain function and to be involved in pathological neurodegenerative disorders such as Alzheimer’s disease (AD). In the present study we investigated the cognitive function in transgenic mice not expressing IL-6 (IL-6 KO) and in wild type (WT) genotype at 4 and 12 months of age, using a passive avoidance and an eight-arm radial maze tasks. Motor function was quantified using an Animex apparatus. Hippocampal choline acetyltransferase (ChAT) activity was evaluated in both genotypes. No difference was observed in both genotypes for spontaneous motor activity. The mean latency (s) to re-enter the shock box, was similar in both young mutant and WT mice. However, a decreased sensitivity (50%) to scopolamine (1 mg/kg) in mutant compared to WT mice, was obtained. IL-6 KO mice exhibited a facilitation of radial maze learning over 30 days, in terms of a lower number of working memory errors and a higher percentage of animals reaching the criterion as compared with WT genotype tested at both ages. Furthermore, mutant mice, at the age of 12 months, showed a faster acquisition (22 days versus 30 days to reach the criterion). The pattern of arm entry exhibited by IL-6 KO mice showed a robust tendency to enter an adjacent arm at both ages, while WT only at the age of 4 months. ChAT activity was inversely correlated with memory performance. These findings suggest a possible involvement of IL-6 on memory processes, even if the mechanism remains still unclear. © 2004 Elsevier B.V. All rights reserved. Keywords: Working memory; Reference memory; Knock out mice; Interleukin-6 1. Introduction Interleukin-6 (IL-6) is a plurifunctional cytokine impli- cated in the regulation of multiple aspects of immune re- sponse, 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 de- generation and cell death in disorders such as Alzheimer’s disease [24]. ∗ Corresponding author. Tel.: +39-02-50317042; fax: +39-02-50317036. E-mail address: mariaelvina.sala@unimi.it (M. Sala). 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 disor- ders including AIDS dementia and Alzheimer’s disease [4]. Furthermore, overexpression of IL-6 in the brain of trans- genic 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 accel- erated 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, lit- tle is known and the evidence obtained often contradictory. An improvement of scopolamine-induced cognitive deficit 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2003.12.018