The age-related attenuation in long-term potentiation is associated with microglial activation Rebecca Griffin, Rachel Nally, Yvonne Nolan, Yvonne McCartney, James Linden and Marina A. Lynch Trinity College Institute for Neuroscience and Physiology Department, Trinity College, Dublin, Ireland Abstract It is well established that inflammatory changes contribute to brain ageing, and an increased concentration of proinflam- matory cytokine, interleukin-1b (IL-1b), has been reported in the aged brain associated with a deficit in long-term potenti- ation (LTP) in rat hippocampus. The precise age at which changes are initiated is unclear. In this study, we investigate parallel changes in markers of inflammation and LTP in 3-, 9- and 15-month-old rats. We report evidence of increased hippocampal concentrations of the proinflammatory cytokines IL-1a, IL-18 and interferon-c (IFNc), which are accompanied by deficits in LTP in the older rats. We also show an increase in expression of markers of microglial activation, CD86, CD40 and intercellular adhesion molecules (ICAM). Associated with these changes, we observed a significant impairment of hip- pocampal LTP in the same rats. The importance of microglial activation in the attenuation of long-term potentiation (LTP) was demonstrated using an inhibitor of microglial activation, minocycline; partial restoration of LTP in 15-month-old rats was observed following administration of minocycline. We propose that signs of neuroinflammation are observed in middle age and that these changes, which are characterized by microglial activation, may be triggered by IL-18. Keywords: age, interferon-c, interleukin-1b, interleukin-18, long-term potentiation, microglial activation. J. Neurochem. (2006) 99, 1263–1272. Interleukin-1b (IL-1b) is a proinflammatory cytokine that probably exerts actions on all organs in the body, and whereas its original proposed role was to activate the immune response, it is now known to play an important role in neuronal function. IL-1b is the most studied of the cytokines in the brain, where its constitutive expression is low but is rapidly up-regulated in response to stress. Consistently increased IL-1b concentration has been observed in experimentally induced trauma, infection and ischaemia (Rock et al. 2004). The evidence suggests that IL- 1b and the subsequent interaction with its signalling receptor, IL-1 receptor type I, induces a downstream signalling cascade which induces the neurotoxicity associated with these conditions. Evidence suggests that the cell source of IL-1b in the brain is likely to be activated microglia (Li et al. 1997; Davies et al. 1999; Minogue et al. 2003) and, in support of this, microglial activation has been shown to occur in experimentally induced stress and in animal models of neurodegenerative diseases (Streit et al. 2004). Microglial activation can be triggered by a range of factors, including activators of Toll-like receptors and inflammatory cytokines such as the interferons (IFNs) and IL-18 (Rock et al. 2004). However, although an increase in the activation state of microglia, accompanied by increased concentrations of inflammatory mediators, is a consistent finding in neurode- generative conditions, the trigger leading to activation in these conditions remains to be identified. Activated microglia release several cytokines and chem- okines, and the increased expression of IL-1b (Murray and Lynch 1998a; Maher et al. 2005) and IL-6 (Godbout and Johnson 2004) in the aged brain suggests that the activation state of microglia should increase with age. Although this has been reported in primates (Sloane et al. 1999), the evidence supporting a similar increase in rodents is less convincing (Perry et al. 1993; Hauss-Wegrzyniak et al. 1999; Kullberg et al. 2001). Interestingly, analysis of phenotype in cultures prepared from aged rats indicated an increased expression of Received April 7, 2006; revised manuscript received July 3, 2006; accepted August 2, 2006. Address correspondence and reprint requests to Marina A. Lynch, Trinity College Institute for Neuroscience and Physiology Department, Trinity College, Dublin 2, Ireland. E-mail: lynchma@tcd.ie Abbreviations used: Epsp, excitatory post-synaptic potential; ICAM, intracellular adhesion molecules; IFN-c, interferon-c; IL-1b, interleukin- 1b; IL-18, interleukin-18; LTP, long-term potentiation; MHC, major histocompatibility complex. Journal of Neurochemistry , 2006, 99, 1263–1272 doi:10.1111/j.1471-4159.2006.04165.x Ó 2006 The Authors Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2006) 99, 1263–1272 1263